Pyrrole derivatives as pharmaceutical agents

ABSTRACT

Novel pyrrazole derivative compounds and their use as pharmaceutical agents, in particular their use as TGF-beta signal transduction inhibitors. The disclosed invention relates to compounds of the structure (I) wherein (I) is a four, five, or six membered saturated ring and X is C, O or S

This application claims the benefit of provisional application60/293,464 filed May 24, 2001.

The invention relates to new pyrrole derivative compounds and their useas pharmaceutical agents, in particular their use as TGF-beta signaltransduction inhibitors.

BACKGROUND OF THE INVENTION

The transforming growth factor-beta (TGF-Beta) (“TGF-β”) polypeptidesinfluence growth, differentiation, and gene expression in many celltypes. The first polypeptide of this family that was characterized,TGF-β1, has two identical 112 amino acid subunits that are covalentlylinked. TGF-β1 is a highly conserved protein with only a single aminoacid difference distinguishing humans from mice. There are two othermembers of the TGF-β gene family that are expressed in mammals. TGF-β2is 71% homologous to TGF-β1 (de Martin, et al., (1987) EMBO J6:3673-3677), whereas TGF-β3 is 80% homologous to TGF-β1 (Derynck, etal. (1988) EMBO J. 7:3737-3743). The structural characteristics ofTGF-β1 as determined by nuclear magnetic resonance (Archer, et al.(1993) Biochemistry 32:1164-1171) agree with the crystal structure ofTGF-β2 (Daopin, et al. (1992) Science 257:369-374; Schlunegger andGrutter (1992) Nature 358:430-434).

There are at least three different extracellular TGF-β receptors, TypeI, II and III that are involved in the biological functions of TGF-β1,-β2 and -β3 (For reviews, see Derynck (1994) TIBS 19:548-553 andMassague (1990) Ann. Rev. Cell Biol. 6:597-641). The Type I and Type IIreceptors are transmembrane serine/threonine kinases which in thepresence of TGF-β form a heteromeric signaling complex (Wrana, et al(1992) Cell 71: 1003-1014).

The mechanism of activation of the heteromeric signaling complex at thecell surface has been elucidated (Wrana, et al. (1994) Nature 370:341-347). TGF-β first binds the type II receptor that is aconstitutively active transmembrane serine/threonine kinase. The type Ireceptor is subsequently recruited into the complex, phoshorylated atthe GS domain and activated to phosphorylate downstream signalingcomponents (e.g. Smad proteins) to initiate the intracellular signalingcascade. A constitutively active type I receptor (T204D mutant) has beenshown to effectively transduce TGF-β responses, thus bypassing therequirement for TGF-β and the type II receptor (Wieser, et al. (1995)EMBO J 14: 2199-2208). Although no signaling function has beendiscovered for the type III receptor, it does increase TGF-β2's affinityfor the type II receptor making it essentially equipotent with TGF-β1and TGF-β3 (Lopez-Casillas, et al. (1993) Cell 73: 1435-1444).

Vascular endothelial cells lack the Type III receptor. Insteadendothelial cells express a structurally related protein called endoglin(Cheifetz, et al., (1992) J. Biol. Chem. 267:19027-19030), which onlybinds TGF-β1 and TGF-β3 with high affinity. Thus, the relative potencyof the TGF-β's reflects the type of receptors expressed in a cell andorgan system. In addition to the regulation of the components in themulti-factorial signaling pathway, the distribution of the synthesis ofTGF-β polypeptides also affects physiological function. The distributionof TGF-β2 and TGF-β3 is more limited (Derynck, et al. (1988) EMBO J.7:3737-3743) than TGF-β1, e.g., TGF-β3 is limited to tissues ofmesenchymal origin, whereas TGF-β1 is present in both tissues ofmesenchymal and epithelial origin.

TGF-β1 is a multifunctional cytokine critical for tissue repair. Highconcentrations of TGF-β1 are delivered to the site of injury by plateletgranules (Assoian and Sporn (1986) J. Cell Biol. 102:1217-1223). TGF-β1initiates a series of events that promote healing including chemo taxisof cells such as leukocytes, monocytes and fibroblasts, and regulationof growth factors and cytokines involved in angiogenesis, cell divisionassociated with tissue repair and inflammatory responses. TGF-β1 alsostimulates the synthesis of extracellular matrix components (Roberts, etal. (1986) Proc. Natl. Acad. Sci. USA 83:4167-4171; Sporn, et al. (1983)Science 219:1329-1330; Massague (1987) Cell 49:437-438) and mostimportantly for understanding the pathophysiology of TGF-β1, TGF-β1autoregulates its own synthesis (Kim, et al. (1989) J. Biol. Chem.264:7041-7045).

SUMMARY OF THE INVENTION

The disclosed invention relates to compounds of the structure:

is a four, five, or six membered saturated ring and X is C, O or S;

R1 is unsubstituted or substituted phenyl; unsubstituted or substitutedpyridine; unsubstituted or substituted pyridine N-oxide; unsubstitutedor substituted quinoline; unsubstituted or substituted quinolineN-oxide; unsubstituted or substituted naphthyridine; unsubstituted orsubstituted pyrazine; furyl; unsubstituted or substituted thiazolyl;unsubstituted or substituted imidazolyl; unsbustituted or substitutedpyrazolyl; or unsbustituted or substituted thiophenyl; wherein thesubstitution may be one or more of the following: (C1-C6)alkyl,(C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C2-C6)alkenyloxy,(C2-C6)alkynyloxy, (C1-C6)alkylthio, (C1-C6)alkylsulphinyl,(C1-C6)alkylsulphonyl, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino,(C1-C6)alkoxycarbonyl, N—(C1-C6)alkylcarbamoyl,N,N-di-[(C1-C6)alkyl]carbamoyl, (C2-C6)alkanoyl, (C2-C6)alkanoyloxy,(C2-C6)alkanoylamino, N—(C1-C6)alkyl-(C2-C6)alkanoylamino,(C3-C6)alkenoylamino, N—(C1-C6)alkyl-(C3-C6)alkenoylamino,(C3-C6)alkynoylamino, N—(C1-C6)alkyl-(C3-C6)alkynoylamino,N—(C1-C6)alkylsulphamoyl, N,N-di-[(C1-C6)alkyl]sulphamoyl,(C1-C6)alkanesulphonylamino, N—(C1-C6)alkyl-(C1-C6)alkanesulphonylamino,carboxamide, ethylene, thiophenyl, aminophenyl, trifluoromethyl, halo,trifluoromethoxy, hydroxymethyl, N-pyrrolidino, N-morpholino,phenylthio, (C1-C4)dialkylaminomethyl, methoxyphenyl, amino, hydroxy,carboxyl, phenyl, arylalky;

R2 is unsubstituted or substituted quinoline; unsbustituted orsubstituted quinoline N-oxide; unsbustituted or substituted phenyl;unsubstituted or substituted naphthalene; unsubstituted or substitutedpyridine; unsubstituted or substituted pyridine N-oxide; unsbustitutedor substituted quinazoline; unsubstituted or substituted cinnoline;unsubstituted or substituted benzodioxole; unsbustituted or substitutedbenzodioxane; unsubstituted or substituted pyrimidine; unsubstituted orsubstituted benzothiophene; or unsubstituted or substitutedphenanthrolene; wherein the substitution may independently be one ormore of the following: hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl,(C2-C6)alkynyl, (C1-C6)alkylhalide, (C1-C6)alkoxy, (C2-C6)alkenyloxy,(C2-C6)alkynyloxy, (C1-C6)alkylthio, (C1-C6)alkylsulphinyl,(C1-C6)alkylsulphonyl, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino,(C1-C6)alkoxycarbonyl, N—(C1-C6)alkylcarbamoyl,N,N-di-[(C1-C6)alkyl]carbamoyl, aminooxy, N—(C1-C6)alkyl aminooxy,N,N-di-[(C1-C6)alkyl]aminooxy, (C2-C6)alkanoyl, (C2-C6)alkanoyloxy,(C2-C6)alkanoylamino, N—(C1-C6)alkyl-(C2-C6)alkanoylamino,(C3-C6)alkenoylamino, N—(C1-C6)alkyl-(C3-C6)alkenoylamino,(C3-C6)alkynoylamino, N—(C1-C6)alkyl-(C3-C6)alkynoylamino, sulphamoyl,N—(C1-C6)alkylsulphamoyl, N,N-di-[(C1-C6)alkyl]sulphamoyl,(C1-C6)alkanesulphonylamino, N—(C1-C6)alkyl-(C1-C6)alkanesulphonylamino,carboxamide, ethylene, phenyl, thiophenyl, aminophenyl, phenylthio,halo, cyano, pyridinyl, arylalkyl, hydroxy, N-pyrrolidino, N-morpholino,carboxyl, [5-phenyl-1,2,4-oxadiazole-3-yl]methoxy,6-methyl-pyridazin-3-yloxy, (5-oxo-2-pyrrolidinyl)methoxy,2-(4,5-dihydro-1H-imidazolyl), N,N-dialkylcarbamoyloxy,1-hydroxy-1-methylethyl, 4-fluorophenyl, 3,4-methylenedioxyphenyl,trifluoromethyl, trifluoromethoxy,or a group of the formula

wherein: X₁ is O, N, S, SO₂, NR₁₃, C(O), or bond; Q₁ is hydrogen,phenyl, 5-(2,2-difluoro-1,3-benzodioxolyl), C(O)Q₅, or pyridyl when mand n are independently 0-2, except when one is 0 the other cannot be 0;Q₁ is OR₁₁, NR₁₁R₁₂, halo, N-morpholino, N-piperazino-N′R₁₃,N-imidazolyl, N-pyrazolyl, N-triazolyl, N-(4-piperidinylpiperidine),SO₂R₁₄, SOR₁₄, NHSO₂R₁₅, acetamido, N-phthalimido, N-oxazolidino,N-imidazolino, N-benzoxazolidino, N-pyrolidinonyl,N(N′-methylbenzimidazolino), N,N-di(C1-C4)alkylamino(C1-C4)alkoxy,N-benzimidazolino; when m and n are independently 0-2, but one or theother of m or n is not 0; Q₅ is hydroxy, methoxy, amino, diethylamino,dimethylamino; R₁₀ is hydrogen, halo, (C1-C6)alkyl; R₁₁ and R₁₂ areindependently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, arylalkyl,(C3-C8)cycloalkyl, (C3-C8)cycloalkylmethyl, 4-(N-methylpiperidinyl),pyridyl, or R₁₁ and R₁₀ can be taken together to form a 4, 5, 6, or 7membered ring, or R₁₁ and R₁₂ can be taken together to form a 3, 4, 5,6, or 7 membered ring; R₁₃ is hydrogen, (C1-C6)alkyl, 2-methoxyphenyl,2-pyridimidinyl; R₁₄ is 2-pyrimidinyl, N-methyl-2-imidazolyl,4-chlorophenyl, 2-pyridylmethyl; R₁₅ is (C1-C6)alkyl,N-methyl-4-imidazolyl; R₁₆ is hydrogen, halo, arylalkyl, aryl,or a group of the formula

wherein: Q₂ is hydrogen, 4-imidazolyl, or C(O)NR₂₄R₂₅ when o and p areindependently 0-2; Q₂ is OR₂₃, NR₂₄R₂₅, or N-morpholino, when o and pare independently 0-2, but one or the other of o or p is not 0; R₂₀ ishydrogen, or (C1-C6)alkyl; R₂₁ is hydrogen, (C1-C6)alkyl, or R₂, and R₂₀can be taken together to form a 4, 5, 6, or 7 membered ring; R₂₂ ishydrogen, (C1-C6)alkyl, arylalkyl, aryl, or R₂, and R₂₂ can be takentogether to be a 3, 4, 5, 6, 7 membered ring; R₂₃ is hydrogen or(C1-C6)alkyl; R₂₄ is hydrogen, (C1-C6)alkyl, or R₂₄ and R₂₅ can be takentogether to form a 3, 4, 5, 6, or 7 membered: ring, or R₂₄ and R₂₀ canbe taken together to form a 6 or 7 membered ring; R₂₅ is hydrogen,(C1-C6)alkyl, or acetyl,or a group of the formula

wherein: R₃₀ is hydrogen, or (C1-C6)alkyl; R₃₁ is hydrogen,(C1-C6)alkyl, 2-pyridyl, pyridylmethyl, amino, or hydroxy,or a group of the formula—NR₃₂R₃₃wherein: R₃₂ and R₃₃ are each independently hydrogen, (C1-C6)alkyl,acetyl, (C1-C4)alkylsulphonyl, or R₃₂ and R₃₃ can be taken together toform a 4, 5, 6, or 7 membered ring,or a group of the formula

wherein: X₂ is CH₂, O, or N; q: is 2-3 except when Q₃ is a bond, q is0-3; Q₃ is NR₃₆R₃₇, or OR₃₈, and R₃₅ is hydrogen, or R₃₅ and Q₃ can betaken together to form a 5 membered ring; R₃₆, R₃₇, and R₃₈ are eachindependently hydrogen, or (C1-C6)alkyl,or a group of the formula

wherein: X₃ is cyano, carboxamide, N,N-dimethylcarboxamide,N,N-dimethylthiocarboxamide, N,N-dimethylaminomethyl,4-methylpiperazin-1yl-methyl or carboxylate,or a group of the formula

wherein: Q₆ is N₁R₄₁R₄₂; r is 2-3; R₄₀ is hydrogen, or (C1-C6)alkyl;R₄₁, and R₄₂ are hydrogen, (C1-C6)alkyl, or R₄₁, and R₄₀ can be takentogether to form a 6 or 7 membered ring,or a group of the formula

wherein: Q₇ is hydroxy, methoxy, dimethylamino, or N-piperidinyl;with the proviso that when one of R1 or R2 is unsubtituted orsubstituted phenyl, then the other cannot be unsubstituted orsubstituted phenyl or thiophen-2-yl; and with the proviso that when R2is quinolin-4-yl, substitution at the quinoline 7-position cannotinclude an aryl, heteroaryl, fused aryl, or fused heteroaryl;k is 1-8; R3 is one or more of the following: hydrogen; (C1-C4)alkyl;(C1-C4)alkylhydroxy; hydroxy; N,N-di(C1-C4)alkylamino(C1-C4)alkoxy;benzyl oxymethyl; phenyloxymethyl; oxo; carboxyl; (C1-C4)alkylaryl;benzyloxy; acetoxy; amino(C1-C4)alkyl; (C2-C4)alkenyl; halo;—O—(C1-C4)alkyl; chlorophenethyl; acetonitrile; unsubsituted orsubstituted phenyl; wherein the substitution may be one or more of thefollowing: (C1-C6)alkoxy, halo, carboxy, or (C1-C6)alkoxycarbonyl; andthe pharmaceutically acceptable salts, esters and prodrugs thereof.

DETAILED DESCRIPTION OF THE INVENTION

The term “effective amount” as used in “an effective amount of acompound of Formula I,” for example, refers to an amount of a compoundof the present invention that is capable of inhibiting TGF beta.

The general chemical terms used herein have their usual meanings. Forexample, as used herein, the term “C₁-C₄ alkyl”, alone or incombination, denotes a straight-chain or branched-chain C₁-C₄ alkylgroup consisting of carbon and hydrogen atoms, examples of which aremethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and thelike. The term “geminal dimethyl” represents two methyl groups attachedat the same substitution position. The term “C₃-C₆ cycloalkyl” refers tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The term “spiro-fusedC₃-C₆ cycloalkyl” refers to a C₃-C₆ cycloalkyl group as defined abovebonded to a carbon atom through a spiro linkage.

The term “C₁-C₄ alkoxy”, alone or in combination, denotes an alkyl groupas defined earlier, which is attached via an oxygen atom, such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, andthe like. The term “C₁-C₄ alkylthio”, alone or in combination, denotesan alkyl group as defined earlier and is attached via a sulfur atom, andincludes methylthio, ethylthio, isobutylthio, and the like.

As used herein, the term “halo” or “halogen” represents fluorine,chlorine, bromine, or iodine. The term “hydroxy,” alone or incombination, represents an —OH moiety. The term “carboxy” or “carboxyl”refers to a carboxylic acid. The term “carboxamide” refers to a carbonylsubstituted with an —NH₂ moiety. The term “oxo” refers to a carbonylgroup.

As used herein, the term “heteroaryl” means an aryl moiety, whichcontains 1-5 heteroatoms selected from O, S, and N. Examples ofheteroaryl groups include pyrrolyl, pyrazolyl, pyranyl, thiopyranyl,furanyl, imidazolyl, pyridyl, thiazolyl, triazinyl, phthalimidyl,indolyl, purinyl, and benzothiazolyl.

As used herein, the term “aryl” represents a substituted orunsubstituted phenyl or naphthyl. Aryl may be optionally substitutedwith one or more groups independently selected from hydroxy, carboxy,C₁-C₆ alkoxy, C₁-C₆ alkyl, halogen, carboxamide, trifluoromethyl,hydroxymethyl, and hydroxy(C₁-C₄)alkyl.

The term “C₃-C₈ cycloalkyl” refers to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term“optionally substituted C₃-C₈ cycloalkyl” refers to a C₃-C₈ cycloalkylas defined herein unsubstituted or substituted with one or more groupsindependently selected from hydroxy, carboxy, C₁₋₆ alkoxy, C₁₋₆ alkyl,halogen, carboxamide, trifluoromethyl, hydroxymethyl, andhydroxy(C₁-C₄)alkyl.

As used herein, the term “saturated heterocycle” is taken to be a 4-9membered ring containing nitrogen and optionally one other atom selectedfrom oxygen, nitrogen, and sulfur. The term “optionally substitutedsaturated heterocycle” is taken to be a saturated heterocycle as definedherein unsubstituted or substituted with one or more groupsindependently selected from hydroxy, carboxy, C₁₋₆ alkoxy, C₁₋₆ alkyl,halogen, carboxamide, trifluoromethyl, hydroxymethyl, andhydroxy(C₁-C₄)alkyl.

As used herein, the term “C₁-C₆ alkyl” refers to straight or branched,monovalent, saturated aliphatic chains of 1 to 6 carbon atoms andincludes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term “C₁-C₆alkyl” includes within its definition the terms “C₁-C₄ alkyl” and “C₁-C₃alkyl.”

“C₁-C₆ alkenyl” refers to a straight or branched, divalent, unsaturatedaliphatic chain of 1 to 6 carbon atoms and includes, but is not limitedto, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl,isobutylenyl, 1-butylenyl, pentylenyl, isopentylenyl, hexylenyl.

“C₁-C₆ alkoxycarbonyl” represents a straight or branched C₁-C₆ alkoxychain, as defined above, that is attached via the oxygen atom to acarbonyl moiety. Typical C₁-C₆ alkoxycarbonyl groups includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, 1-butoxycarbonyl and the like.

The term “di(C₁-C₆ alkyl)amino” refers to a group of the formula:

wherein each R group independently represents a “C₁-C₆ alkyl” group, asdefined above.

An “optionally substituted phenyl” is a phenyl ring that isunsubstituted or substituted with 1 to 5 substituents, more preferably 1to 3 substituents, for example: halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkylamino, trifluoromethyl, nitro, and cyano.

An “optionally substituted benzyl” is a benzyl ring that isunsubstituted or substituted with 1 to 5 substituents, more preferably 1to 3 substituents, for example: halo, C₁-C₆ alkyl, C₁-C₆ alkoxy,trifluoromethyl, nitro, and cyano.

“Phenoxycarbonyl” refers to the group: phenyl-O—C(O)—. “Aryl” refers toan unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms havinga single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g.,naphthyl or anthracenyl).

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1 to 5 substituents,more preferably 1 to 3 substituents, selected from the group consistingof halo, hydroxy, acetyl, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy,phenyl, di(C₁-C₆ alkyl)amino, trifluoromethyl, trifluoromethoxy,—S(O)_(m)—(C₁-C₆ alkyl), and —S(O)_(m)-(phenyl), wherein m can be 0, 1,or 2.

“Arylalkyl” refers to aryl groups attached to alkyl groups, preferablyhaving 1 to 6 carbon atoms in the alkyl moiety and 6 to 10 carbon atomsin the aryl moiety. Such arylalkyl groups are exemplified by benzyl,phenethyl, and the like.

Unless otherwise constrained by the definition for arylalkyl, sucharylalkyl groups can be optionally substituted with 1 to 5 substituents,more preferably 1 to 3 substituents, selected from the group consistingof halo, hydroxy, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy, di(C₁-C₆alkyl)amino, trifluoromethyl, trifluoromethoxy, carbamoyl, pyrrolidinyl,—S(O)_(m)—(C₁-C₆ alkyl), and —S(O)_(m)-(phenyl), wherein m can be 0, 1,or 2. The arylalkyl groups may be optionally substituted on the arylmoiety, the alkyl moiety, or both the aryl moiety and the alkyl moiety.

The term “heterocycle” represents an unsubstituted or substituted 5- to7-membered monocyclic, or 7- to 11-membered bicyclic heterocyclic ringthat is saturated or unsaturated and that consists of carbon atoms andfrom one to five heteroatoms selected from the group consisting ofnitrogen, oxygen or sulfur, and including a bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring toanother heterocycle as defined above.

The term “heteroaryls” represents the above-defined heterocylic ringsthat are fused to a benzene ring to another heterocycle as definedabove.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocycles can be optionally substituted with 1 to 8substituents selected from the group consisting of halo, nitro, cyano,hydroxy, acetyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₁₀ cycloalkyl,optionally substituted phenyl, phenethyl, phenoxy, phenoxycarbonyl,optionally substituted benzyl, 1,1-diphenylmethyl, oxo, C₁-C₆alkoxycarbonyl, (C₁-C₆ alkoxy)C₁-C₆ alkyl-, trifluoromethyl, pyridyl,(pyrrolidinyl)C₁-C₆ alkyl-, and (pyridyl)C₁-C₆ alkyl-, di(C₁-C₆alkyl)amino, trifluoromethyl, trifluoromethoxy, —S(O)_(m)—(C₁-C₆ alkyl),and —S(O)_(m)-(phenyl), wherein m can be 0, 1, or 2.

Examples of such heterocycles include azepinyl, azetidinyl,benzazepinyl, benzimidazolyl, benzoazolyl, benzodioxolyl, benzodioxanyl,benzopyranyl, benzothiazolyl, benzothienyl, dihydropyrazolooxazinyl,dihydropyrazolooxazolyl, furyl, imidazolyl, imidazolinyl,imidazolidinyl, indolinyl, indolyl, isoindolinyl, isoquinolinyl,isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl,napthyridinyl, oxadiazolyl, oxazolyl, oxazolidinyl, phthalimidyl,piperazinyl, piperidinyl, pyrazinyl, pyridyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolidinyl,pyrrolopyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydropyranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiazolinyl, thiazolidinyl,thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, and the like.

Preferred heterocycles include: benzodioxolyl, dihydropyrrolopyrazolyl,pyridyl, quinolinyl.

Preferred embodiments of the invention include the following:

One preferred embodiment of the invention are compounds of thestructure:

is a five or six membered saturated ring with the proviso that the ringis a fully saturated carbon ring;

R1 is defined as in claim 1;

R2′ is hydrogen; (C1-C6)alkyl; (C1-C6)alkylthio; (C1-C6)alkoxy; halo;thiophenyl; aminophenyl; N-pyrrolidino; N-morpholino;

R6′ and R7′ are independently one or more of the following: hydrogen,(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalide,(C1-C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C1-C6)alkylthio,(C1-C6)alkylsulphinyl, (C1-C6)alkylsulphonyl, (C1-C6)alkylamino,di-[(C1-C6)alkyl]amino, (C1-C6)alkoxycarbonyl, N—(C1-C6)alkylcarbamoyl,N,N-di-[(C1-C6)alkyl]carbamoyl, aminooxy, N—(C1-C6)alkyl aminooxy,N,N-di-[(C1-C6)alkyl]aminooxy, (C2-C6)alkanoyl, (C2-C6)alkanoyloxy,(C2-C6)alkanoylamino, N—(C1-C6)alkyl-(C2-C6)alkanoyl amino,(C3-C6)alkanoyl amino, N—(C1-C6)alkyl-(C3-C6)alkenoylamino,(C3-C6)alkynoylamino, N—(C1-C6)alkyl-(C3-C6)alkynoylamino, sulphamoyl,N—(C1-C6)alkylsulphamoyl, N,N-di-[(C1-C6)alkyl]sulphamoyl,(C1-C6)alkanesulphonylamino, N—(C1-C6)alkyl-(C1-C6)alkanesulphonylamino,carboxamide, ethylene, phenyl, thiophenyl, aminophenyl, phenylthio,halo, cyano, pyridinyl, arylalkyl, hydroxy, N-pyrrolidino, N-morpholino,carboxyl, [5-phenyl-1,2,4-oxadiazole-3-yl]methoxy,6-methyl-pyridazin-3-yloxy, (5-oxo-2-pyrrolidinyl)methoxy,2-(4,5-dihydro-1H-imidazolyl), N,N-dialkylcarbamoyloxy,1-hydroxy-1-methylethyl, 4-fluorophenyl, 3,4-methylenedioxyphenyl,trifluoromethyl, trifluoromethoxy,or a group of the formula

wherein: X₁ is O, N, S, SO₂, NR₁₃, C(O), or bond, Q₁ is hydrogen,phenyl, 5-(2,2-difluoro-1,3-benzodioxolyl), C(O)Q₅, or pyridyl when mand n are independently 0-2, except when one is 0 the other cannot be 0;Q₁ is OR₁₁, NR₁₁R₁₂, halo, N-morpholino, N-piperazino-N′R₁₃,N-imidazolyl, N-pyrazolyl, N-triazolyl, N-(4-piperidinylpiperidine),SO₂R₁₄, SOR₁₄, NHSO₂R₁₅, acetamido, N-phthalimido, N-oxazolidino,N-imidazolino, N-benzoxazolidino, N-pyrolidinonyl,N(N′-methylbenzimidazolino), N,N-di(C1-C4)alkylamino(C1-C4)alkoxy,N-benzimidazolino; when m and n are independently 0-2, but one or theother of m or n is not 0; Q₅ is hydroxy, methoxy, amino, diethylamino,dimethylamino; R₁₀ is hydrogen, halo, (C1-C6)alkyl; R₁₁ and R₁₂ areindependently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, arylalkyl,cycloalkyl, cycloalkylmethyl, 4-(N-methylpiperidinyl), pyridyl, or R₁₁and R₁₀ can be taken together to form a 4, 5, 6, or 7 membered ring, orR₁₁ and R₁₂ can be taken together to form a 3, 4, 5, 6, or 7 memberedring; R₁₃ is hydrogen, (C1-C6)alkyl, 2-methoxyphenyl; R₁₄ is2-pyrimidinyl, N-methyl-2-imidazolyl, 4-chlorophenyl, 2-pyridylmethyl;R₁₅ is (C₁-C6)alkyl, N-methyl-4-imidazolyl; R₁₆ is hydrogen, halo,arylalkyl, aryl,or a group of the formula

wherein: Q₂ is hydrogen, 4-imidazolyl, or C(O)NR₂₄R₂₅ when o and p areindependently 0-2; Q₂ is OR₂₃, NR₂₄R₂₅, or N-morpholino, when o and pare independently 0-2, but one or the other of o or p is not 0; R₂₀ ishydrogen, or (C1-C6)alkyl; R₂₁ is hydrogen, (C1-C6)alkyl, or R₂₁ and R₂₀can be taken together to form a 4, 5, 6, or 7 membered ring; R₂₂ ishydrogen, (C1-C6)alkyl, arylalkyl, aryl, or R₂₁ and R₂₂ can be takentogether to be a 3, 4, 5, 6, 7 membered ring; R₂₃ is hydrogen or(C1-C6)alkyl; R₂₄ is hydrogen, (C1-C6)alkyl, or R₂₄ and R₂₅ can be takentogether to form a 3, 4, 5, 6, or 7 membered ring, or R₂₄ and R₂₀ can betaken together to form a 6 or 7 membered ring; R₂₅ is hydrogen,(C1-C6)alkyl, or acetyl,or a group of the formula

wherein: R₃₀ is hydrogen, or (C1-C6)alkyl; R₃₁ is hydrogen,(C1-C6)alkyl, 2-pyridyl, pyridylmethyl, amino, or hydroxy,or a group of the formula—NR₃₂R₃₃wherein: R₃₂ and R₃₃ are each independently hydrogen, (C1-C6)alkyl,acetyl, alkylsulphonyl, or R₃₂ and R₃₃ can be taken together to form a4, 5, 6, or 7 membered ring,or a group of the formula

wherein: X₂ is CH₂, O, or N; q is 2-3 except when Q₃ is a bond, q is0-3; Q₃ is NR₃₆R₃₇, OR₃₈, or a bond; R₃₅ is hydrogen, or R₃₅ and Q₃(when Q₃ is a bond) can be taken together to form a 5 membered ring;R₃₆, R₃₇, and R₃₈ are each independently hydrogen, or (C1-C6)alkyl,or a group of the formula

wherein: X₃ is cyano, carboxamide, N,N-dimethylcarboxamide,N,N-dimethylthiocarboxamide, N,N-dimethylaminomethyl,4-methylpiperazin-1yl-methyl or carboxylate,or a group of the formula

wherein: Q₆ is NR₄₁R₄₂; r is 2-3; R₄₀ is hydrogen, or (C1-C6)alkyl; R₄₁and R₄₂ are hydrogen, (C1-C6)alkyl, or R₄₁ and R₄₀ can be taken togetherto form a 6 or 7 membered ring,or a group of the formula

wherein: Q₇ is hydroxy, methoxy, or N-piperidinyl;

k is 1-8; R3 is one or more of the following: hydrogen; (C1-C4)alkyl;(C1-C4) alkylhydroxy; hydroxy; N,N-di(C1-C4)alkylamino(C1-C4)alkoxy;benzyl oxymethyl; phenyloxymethyl; oxo; carboxyl; (C1-C4)alkylaryl;benzyloxy; acetoxy; amino(C1-C4)alkyl; (C2-C4)alkenyl; halo;—O—(C1-C4)alkyl; chlorophenethyl; acetonitrile; phenyl; or an optionallysubstituted phenyl; wherein the substitution may be one or more of thefollowing: (C1-C6)alkoxy, halo, carboxy, or (C1-C6)alkoxycarbonyl; withthe proviso that R7′ cannot be aryl; heteroaryl; fused aryl; or fusedheteroaryl, and the pharmaceutically acceptable salts, esters andprodrugs thereof.Another preferred embodiment of the invention are compounds of thestructure:

is a five or six membered saturated ring, with the proviso that the ringis a fully saturated carbon ring;

R1 is defined as in claim 1;

R3″ is hydrogen; halo; trifluoromethyl;

R4″ is hydrogen; halo; (C1-C6)alkyl; (C1-C6)alkoxy; hydroxy;(C1-C6)alkylsulphonyl;

k and R3 are defined as in claim 1;

and the pharmaceutically acceptable salts, esters and prodrugs thereof.Another preferred embodiment of the invention are compounds of thestructure:

is a five or six membered saturated ring, with the proviso that the ringis a fully saturated carbon ring;

R6 may be one or more of the following: hydrogen, (C1-C6)alkyl,(C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C2-C6)alkenyloxy,(C2-C6)alkynyloxy, (C1-C6)alkylthio, (C1-C6)alkylsulphinyl,(C1-C6)alkylsulphonyl, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino,(C1-C6)alkoxycarbonyl, N—(C1-C6)alkylcarbamoyl,N,N-di-[(C1-C6)alkyl]carbamoyl, (C2-C6)alkanoyl, (C2-C6)alkanoyloxy,(C2-C6)alkanoylamino, N—(C1-C6)alkyl-(C2-C6)alkanoylamino,(C3-C6)alkenoylamino, N—(C1-C6)alkyl-(C3-C6)alkenoylamino,(C3-C6)alkynoylamino, N—(C1-C6)alkyl-(C3-C6)alkynoylamino,N—(C1-C6)alkyl sulphamoyl, N,N-di-[(C1-C6)alkyl]sulphamoyl,(C1-C6)alkanesulphonylamino, N—(C1-C6)alkyl-(C1-C6)alkanesulphonylamino,carboxamide, ethylene, thiophenyl, aminophenyl, trifluoromethyl, halo,trifluoromethoxy, hydroxymethyl, N-pyrrolidino, N-morpholino,phenylthio, dialkylaminomethyl, methoxyphenyl, amino, hydroxy, carboxyl,phenyl, arylalky;

R2″ is unsubstituted or substituted quinoline-8-yl; unsubstituted orsubstituted quinoline-6-yl; unsubstituted or substituted 1-naphthyl;unsubstituted or substituted 2-naphthyl; unsubstituted or substituted3,4-methylenedioxyphenyl; unsbustituted or substituted3,4-ethylenedioxyphenyl; unsubstituted or substitutedbenzothiophen-2-yl; wherein the substitution may independently be one ormore of the following: (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,(C1-C6)alkylhalide, (C1-C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy,(C1-C6)alkylthio, (C1-C6)alkylsulphinyl, (C1-C6)alkylsulphonyl,(C1-C6)alkylamino, di-[(C1-C6)alkyl]amino, (C1-C6)alkoxycarbonyl,N—(C1-C6)alkylcarbamoyl, N,N-di-[(C1-C6)alkyl]carbamoyl, aminooxy,N—(C1-C6)alkyl aminooxy, N,N-di-[(C1-C6)alkyl]aminooxy, (C2-C6)alkanoyl,(C2-C6)alkanoyloxy, (C2-C6)alkanoylamino,N—(C1-C6)alkyl-(C2-C6)alkanoylamino, (C3-C6)alkenoylamino,N—(C1-C6)alkyl-(C3-C6)alkenoylamino, (C3-C6)alkynoylamino,N—(C1-C6)alkyl-(C3-C6)alkynoylamino, sulphamoyl,N—(C1-C6)alkylsulphamoyl, N,N-di-[(C1-C6)alkyl]sulphamoyl,(C1-C6)alkanesulphonylamino, N—(C1-C6)alkyl-(C1-C6)alkanesulphonylamino,carboxamide, ethylene, phenyl, thiophenyl, aminophenyl, phenylthio,halo, cyano, pyridinyl, arylalkyl, hydroxy, N-pyrrolidino, N-morpholino,carboxyl, [5-phenyl-1,2,4-oxadiazole-3-yl]methoxy,6-methyl-pyridazin-3-yloxy, (5-oxo-2-pyrrolidinyl)methoxy,2-(4,5-dihydro-1H-imidazolyl), N,N-dialkylcarbamoyloxy,1-hydroxy-1-methylethyl, 4-fluorophenyl, 3,4-methylenedioxyphenyl,trifluoromethyl, trifluoromethoxy,or a group of the formula

wherein: X₁ is O, N, S, SO₂, NR₁₃, C(O), or bond; Q₁ is hydrogen,phenyl, 5-(2,2-difluoro-1,3-benzodioxolyl), C(O)Q₅, or pyridyl when mand n are independently 0-2, except when one is 0 the other cannot be 0;Q₁ is OR₁₁, NR₁₁R₁₂, halo, N-morpholino, N-piperazino-N′R₁₃,N-imidazolyl, N-pyrazolyl, N-triazolyl, N-(4-piperidinylpiperidine),SO₂R₁₄, SOR₁₄, NHSO₂R₁₅, acetamido, N-phthalimido, N-oxazolidino,N-imidazolino, N-benzoxazolidino, N-pyrolidinonyl,N(N′-methylbenzimidazolino), N,N-di(C1-C4)alkylamino(C1-C4)alkoxy,N-benzimidazolino; when m and n are independently 0-2, but one or theother of m or n is not 0; Q₅ is hydroxy, methoxy, amino, diethylamino,dimethylamino; R₁₀ is hydrogen, halo, (C₁-C6)alkyl; R₁₁ and R₁₂ areindependently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, arylalkyl,cycloalkyl, cycloalkylmethyl, 4-N-methylpiperidinyl), pyridyl, or R₁₁and R₁₀ can be taken together to form a 4, 5, 6, or 7 membered ring, orR₁₁ and R₁₂ can be taken together to form a 3, 4, 5, 6, or 7 memberedring; R₁₃ is hydrogen, (C1-C6)alkyl, 2-methoxyphenyl; R₁₄ is2-pyrimidinyl, N-methyl-2-imidazolyl, 4-chlorophenyl, 2-pyridylmethyl;R₁₅ is (C1-C6)alkyl, N-methyl-4-imidazolyl; R₁₆ is hydrogen, halo,arylalkyl, aryl,or a group of the formula

wherein: Q₂ is hydrogen, 4-imidazolyl, or C(O)NR₂₄R₂₅ when o and p areindependently 0-2; Q₂ is OR₂₃, NR₂₄R₂₅, or N-morpholino, when o and pare independently 0-2, but one or the other of o or p is not 0; R₂₀ ishydrogen, or (C1-C6)alkyl; R₂₁ is hydrogen, (C1-C6)alkyl, or R₂, and R₂₀can be taken together to form a 4, 5, 6, or 7 membered ring; R₂₂ ishydrogen, (C1-C6)alkyl, arylalkyl, aryl, or R₂, and R₂₂ can be takentogether to be a 3, 4, 5, 6, 7 membered ring; R₂₃ is hydrogen or(C₁-C6)alkyl; R₂₄ is hydrogen, (C1-C6)alkyl, or R₂₄ and R₂₅ can be takentogether to form a 3, 4, 5, 6, or 7 membered ring, or R₂₄ and R₂₀ can betaken together to form a 6 or 7 membered ring; R₂₅ is hydrogen,(C1-C6)alkyl, or acetyl,or a group of the formula

wherein: R₃₀ is hydrogen, or (C1-C6)alkyl; R₃₁ is hydrogen,(C1-C6)alkyl, 2-pyridyl, pyridylmethyl, amino, or hydroxy,or a group of the formula—NR₃₂R₃₃wherein: R₃₂ and R₃₃ are each independently hydrogen, (C1-C6)alkyl,acetyl, alkylsulphonyl, or R₃₂ and R₃₃ can be taken together to form a4, 5, 6, or 7 membered ring,or a group of the formula

wherein: X₂ is CH₂, O, or N; q is 2-3 except when Q₃ is a bond, q is0-3; Q₃ is NR₃₆R₃₇, OR₃₈, or a bond; R₃₅ is hydrogen, or R₃₅ and Q₃(when Q₃ is a bond) can be taken together to form a 5 membered ring;R₃₆, R₃₇, and R₃₈ are each independently hydrogen, or (C1-C6)alkyl,or a group of the formula

wherein: X₃ is cyano, carboxamide, N,N-dimethylcarboxamide,N,N-dimethylthiocarboxamide, N,N-dimethylaminomethyl,4-methylpiperazin-1yl-methyl or carboxylate,or a group of the formula

wherein: Q₆ is NR₄₁R₄₂; r is 2-3; R₄₀ is hydrogen, or (C1-C6)alkyl; R₄₁and R₄₂ are hydrogen, (C1-C6)alkyl, or R₄₁ and R₄₀ can be taken togetherto form a 6 or 7 membered ring,or a group of the formula

wherein: Q₇ is hydroxy, methoxy, dimethylamino, or N-piperidinyl;

k is 1-8; R3 is hydrogen; and the pharmaceutically acceptable saltsthereof.

Compounds Exemplified in the Application Include the Following:

-   a)    6-Bromo-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   b)    3-Pyridin-4-yl-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   c)    2-(6-Methyl-pyridin-2-yl)-3-p-tolyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   d)    4-[3-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]-quinoline,-   e)    2-(6-Methyl-pyridin-2-yl)-3-naphthalen-1-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   f)    2-(6-Methyl-pyridin-2-yl)-3-pyridin-3-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   g)    3-(4-Fluoro-naphthalen-1-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   h)    3-(3,4-Difluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   i)    1-[2-(4-Methanesulfonyl-phenyl)-1-(6-methyl-pyridin-2-yl)-ethylideneamino]-pyrrolidin-2-one,-   j)    7-Methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   k)    7-Benzyloxy-6-methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   l)    6-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   m)    6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   n)    3-Naphthalen-2-yl-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   o)    2-(6-Methyl-pyridin-2-yl)-3-naphthalen-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   p)    3-(4-Fluoro-phenyl)-2-(6-trifluoromethyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   q)    4-(Quinolin-4-yl)-3-(5-fluoropyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   r)    4-(7-Bromoquinolin-4-yl)-3-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   s)    (Quinolin-4-yl)-3-(2,4-difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   t) 4-(2-Pyrazin-2-yl-5,6-dihydro-4H-pyrrolo    [1,2-b]pyrazol-3-yl)-quinoline,-   u)    4-(5-Methyl-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   v)    6-Bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   w)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-6-trifluoromethyl-quinoline,-   x)    3-(3-Chloro-4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   y)    3-(2-Chloro-4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   z)    3-(4-Fluoro-3-trifluoromethyl-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   aa)    2-(6-Methyl-pyridin-2-yl)-3-(2,4,5-trifluoro-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   bb)    8-Fluoro-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   cc)    7-Bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   dd)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-6-trifluoromethoxy-quinoline,-   ee)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-7-trifluoromethyl-quinoline,-   ff)    7-Methoxy-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   gg)    3-(2-Chloro-pyridin-4-yl)-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   hh)    [2-(6-Methyl-pyridin-2-yl)-3-quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-methanol,-   ii)    [3-(7-Bromo-quinolin-4-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-methanol,-   jj)    4-[2-(6-Chloro-pyridin-2-yl)-5-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   kk)    4-[2-(6-Ethoxy-pyridin-2-yl)-5-(4-fluoro-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   ll)    (S)-4-[6-Benzyloxymethyl-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-7-chloro-quinoline,-   mm)    (S)-4-[6-Benzyloxymethyl-2-(6-chloro-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   nn)    4-[2-(6-Methyl-pyridin-2-yl)-3-quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-5-yl]-benzoic    acid ethyl ester,-   oo)    3-(4-Fluoro-phenyl)-5,5-dimethyl-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   pp)    (R)-6-Benzyloxymethyl-3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   qq)    5-(4-Chloro-phenyl)-3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   rr)    4-[2-(3-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   ss)    4-[2-(4-Trifluoromethyl-phenyl)4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   tt)    4-[2-(4-Chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   uu)    4-[2-(3-Chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-y]-quinoline,-   vv)    4-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   ww)    4-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   xx)    4-(2-Phenyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl)-quinoline,-   yy)    4-(2-Pyridin-2-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl)-[1,10]phenanthroline,-   zz)    4-[2-(4-Fluoro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   aaa)    4-[2-(3-Trifluoromethoxy-phenyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   bbb)    4-[2-(2-Fluoro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   ccc)    4-(2-Quinolin-2-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl)-quinoline,-   ddd)    4-[2-(4-Ethyl-pyridin-2-yl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   eee)    4-(2-Quinolin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   fff)    2-(3-Quinolin-4-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-yl)-[1,8]naphthyridine,-   ggg)    4-[5-(4-Fluoro-phenyl)-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   hhh)    4-(6-Hydroxymethyl-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3yl)-quinoline,-   iii)    4-(3-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-quinoline,-   jjj)    4-(4-Methyl-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   kkk)    4-(5-Benzyl-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   lll)    4-(5-Phenethyl-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   mmm)    4-(5-Phenyl-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   nnn)    4-[2-(3-Trifluoromethylphenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   ooo)    4-[2-(4-Trifluoromethyl-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   ppp)    4-(2-Phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   qqq)    2-Chloro-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   rrr)    6,8-Dimethoxy-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2b]pyrazol-3-yl]-quinoline,-   sss)    4-[2-(6-Bromo-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   ttt)    6,8-Dimethoxy-4-[2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2b]pyrazol-3-yl]-quinoline,-   uuu)    3-(4-Fluorophenyl)-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   vvv)    3-(4-Methoxy-phenyl)-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   www)    3-(4-Fluorophenyl)-2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   xxx)    3-(4-Methoxyphenyl)-2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   yyy)    4-(2-Thiophen-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline,-   zzz)    4-[2-(6-Propylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   aaaa)    4-[2-(6-Isopropylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline,-   bbbb)    4-[2-(6-Ethyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline,-   cccc)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   dddd)    4-[2-(3-Fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   eeee)    4-[2-(2-Fluoro-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   ffff)    4-[2-(4-Fluoro-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   gggg)    4-[2-(3-Trifluoromethoxy-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   hhhh)    4-[2-(4-Chloro-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   iiii)    4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline,-   jjjj)    4-[2-(2-Fluoro-3-trifluoromethyl-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]-pyrazol-3-yl]-quinoline,-   kkkk)    4-[5-(3-Methoxy-phenyl)-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   llll)    4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-5-(3-methoxy-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   mmmm)    4-(7-Chloro-quinolin-4-yl)-3-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   nnnn)    4-(7-Ethoxyquinolin-4-yl)-3-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   oooo)    6-(3-Quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-pyridine-2-carboxylic    acid hydrochloride,-   pppp)    6,7-Difluoro-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   qqqq)    6,7-Dimethoxy-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   rrrr)    3-Benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   ssss)    6-(4-Fluoro-phenyl)-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   tttt)    6-Benzo[1,3]dioxol-5-yl-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   uuuu)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-6-thiophen-2-yl-quinoline,-   vvvv)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-6-phenyl-quinoline,-   wwww)    8-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   xxxx)    3-Benzo[b]thiophen-2-yl-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   yyyy)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-6-carboxylic    acid methyl ester,-   zzzz)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-6-carboxylic    acid methyl ester,-   aaaaa)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic    acid methyl ester,-   bbbbb)    4-[2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic    acid methyl ester,-   ccccc) 2-Pyridin-2-yl-3-quinolin-4-yl-pyrazolo[5,1-c]morpholine,-   ddddd)    2-Pyridin-2-yl-3-quinolin-4-yl-pyrazolo[5,1-c]morpholin-4-one,-   eeeee)    Dimethyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine,-   fffff)    {3-[6-Methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-dimethyl-amine,-   ggggg)    Cyclopropylmethyl-propyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine,-   hhhhh)    Diethyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine,-   iiiii)    Ethyl-methyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine,-   jjjjj)    3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propylamine,-   kkkkk)    7-[3-(4-Methyl-piperazin-1-yl)-propoxy]-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   lllll)    Benzyl-methyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine,-   mmmmm)    7-(3-Piperidin-1-yl-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   nnnnn)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-(3-pyrrolidin-1-yl-propoxy)-quinoline,-   ooooo)    7-(3-Azepan-1-yl-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   ppppp)    7-(3-Imidazol-1-yl-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   qqqqq)    7-(3-Pyrazol-1-yl-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   rrrrr)    1′-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-[1,4′]bipiperidinyl,-   sssss)    Cyclopropyl-(1-methyl-piperidin-4-yl)-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine,-   ttttt)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-(3-[1,2,3]triazol-1-yl-propoxy)-quinoline,-   uuuuu)    Dimethyl-(3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yloxy}-propyl)-amine,-   vvvvv)    Diethyl-(3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yloxy}-propyl)-amine,-   wwwww)    Cyclopropylmethyl-(3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yloxy}-propyl)-propyl-amin,-   xxxxx)    Ethyl-methyl-(3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yloxy}-propyl)-amine,-   yyyyy)    Dimethyl-{2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-ethyl}-amine,-   zzzzz)    Diethyl-{2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-quinolin-7-yloxy]-ethyl}-amine,-   aaaaaa)    7-(2-Piperidin-1-yl-ethoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   bbbbbb)    Ethyl-methyl-{2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]ethyl}-amine,-   cccccc)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-(2-pyrrolidin-1-yl-ethoxy)-quinoline,-   dddddd)    7-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   eeeeee)    Dimethyl-{3-[1-oxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine,-   ffffff)    7-Methylsulfanyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   gggggg)    7-Ethylsulfanyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   hhhhhh)    6-Methylsulfanyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   iiiiii)    7-Benzylsulfanyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   jjjjjj)    3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ylsulfanyl]-propan-1-ol,-   kkkkkk)    Dimethyl-{2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ylsulfanyl]-ethyl}-amine,-   llllll) Dimethyl    [6-(3-quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-pyridin-2-yl-methyl]amine,-   mmmmmm)    7-(2-Propoxy-ethoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   nnnnnn)    N,N-Dimethyl-N′-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-pyridin-2-yl]-ethane-1,2-diamine,-   oooooo)    N,N-Dimethyl-N′-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-pyridin-2-yl]-propane-1,3-diamine,-   pppppp)    3-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-oxazolidin-2-one,-   qqqqqq)    1-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-imidazolidin-2-one,-   rrrrrr)    3-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy)-propyl}-3H-benzooxazol-2-one,-   ssssss)    Dimethyl-(2-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyridin-2-ylsulfanyl}-ethyl-amine,-   tttttt) 4-(2-Pyridin-2-yl-5,6-dihydro-4H    pyrrolo[1,2-b]pyrazol-3-yl)-2pyrrolidin-1-yl-quinoline,-   uuuuuu)    2-Phenylsulfanyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   vvvvvv)    2-Morpholin-4-yl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   wwwwww)    2-Ethylsulfanyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   xxxxxx)    Phenyl-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-2-yl]-amine,-   yyyyyy)    2-Methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   zzzzzz)    2-Ethoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   aaaaaaa)    4-[2-(6-Phenylsulfanyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   bbbbbbb)    Phenyl-[6-(3-quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-pyridin-2-yl]-amine,-   ccccccc)    4-{2-[6-(4-Methoxy-phenyl)-pyridin-2-yl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl}-quinoline,-   ddddddd)    4-[2-(6-Phenyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   eeeeeee)    4-[2-(6-Morpholin-4-yl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   fffffff)    4-[2-(6-Pyrrolidin-1-yl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   ggggggg)    4-[2-(6-Methoxy-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   hhhhhhh)    2-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-isoindole-1,3-dione,-   iiiiiii)    7-(3-Fluoro-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   jjjjjjj)    7-(3-Fluoro-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   kkkkkkk)    7-(3-Chloro-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   lllllll)    7-(3-Chloro-propoxy)-6-methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   mmmmmmm)    7-(3-Chloro-propoxy)-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   nnnnnnn)    (1-{3-[7-(2-Chloro-ethoxy)-quinolin-4-yl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl}-propenyl)-methylene-amine,-   ooooooo)    N,N-Diethyl-2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetamide,-   ppppppp)    7-[2-((2R)-1-Methyl-pyrrolidin-2-yl)-ethoxy]-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   qqqqqqq)    Dimethyl-{4-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-pyridin-2-yloxy]-butyl}-amine,-   rrrrrrr)    1-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-pyridin-2-yloxy]-propyl}-pyrrolidin-2-one,-   sssssss)    7-(1-Methyl-piperidin-3-ylmethoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   ttttttt)    7-(3-N,N-Dimethylamino-2-methyl-propyloxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   uuuuuuu)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-7-propoxy-quinoline,-   vvvvvvv)    4-[6-Benzyloxymethyl-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   wwwwwww)    {4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yloxy}-acetic    acid methyl ester,-   xxxxxxx)    7-Isopropoxy-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   yyyyyyy)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-7-(3-morpholin-4-yl-propoxy)-quinoline,-   zzzzzzz)    4-(6-Benzyloxymethyl-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl)-quinoline,-   aaaaaaaa)    7-Benzyloxy-2-Pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]piperidine,-   bbbbbbbb)    2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetamide,-   cccccccc)    7-(5-Phenyl-[1,2,4]oxadiazol-3-ylmethoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   dddddddd)    7-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   eeeeeeee)    7-[2-((2S)-]-Methyl-pyrrolidin-2-yl)-ethoxy]-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   ffffffff)    5-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxymethyl]-pyrrolidin-2-one,-   gggggggg)    4-(6-Phenoxymethyl-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   hhhhhhhh)    4-(6-Methylene-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   iiiiiiii)    3-(4-Fluoro-phenyl)-6-methylene-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   jjjjjjjj)    7-(1-Methyl-piperidin-2-ylmethoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline    hydrochloride,-   kkkkkkkk)    7-[2-(1-Methyl-pyrrolidin-2-yl)-ethoxy]-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline    hydrochloride,-   llllllll)    4-[2-(6-Methyl-1-oxy-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline    1-oxide,-   mmmmmmmm)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline    1-oxide,-   nnnnnnnn)    4-[2-(6-Methyl-1-oxy-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   oooooooo)    7-(3-Chloro-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline    1-oxide,-   pppppppp)    7-Methanesulfonyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   qqqqqqqq)    3-(4-Fluoro-phenyl)-2-(6-methyl-1-oxy-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   rrrrrrrr)    4-(Quinolin-N1-oxide-4-yl)-3-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   ssssssss)    6-Methanesulfonyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   tttttttt)    7-Ethanesulfonyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   uuuuuuu)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-[3-(pyrimidine-2-sulfonyl)-propoxy]-quinoline,-   vvvvvvvv)    7-[3-(1-Methyl-1H-imidazole-2-sulfonyl)-propoxy]-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   wwwwwwww)    7-[3-(4-Chloro-benzenesulfonyl)-propoxy]-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   xxxxxxxx)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-[3-(pyridin-2-ylmethanesulfonyl)-propoxy]-quinoline,-   yyyyyyyy)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-[3-(pyridin-2-ylmethanesulfinyl)-propoxy]-quinoline,-   zzzzzzzz)    4-(Quinolin-1-N-oxide-4-yl)-3-(6-methylpyridin-2-yl-1-N-oxide)-5,6-dihydro-4H-pyrrolo    [1,2-b]pyrazole,-   aaaaaaaaa)    3-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-acrylic    acid methyl ester,-   bbbbbbbbb) 3-{4-[2-(6-Methylpyridin-2-yl-5,6-dihydro-4H-pyrrolo    [1,2-b]pyrazol-3-yl]quinolin-7-yl}-1-piperidin-1-yl-propenone,-   ccccccccc)    3-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-6-yl}-acrylic    acid methyl ester,-   ddddddddd)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-7-vinyl-quinoline,-   eeeeeeeee)    4-[2-(6-Benzyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   fffffffff)    7-Benzyl-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   ggggggggg)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic    acid,-   hhhhhhhhh)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-6-carboxylic    acid,-   iiiiiiiii)    3-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-acrylic    acid,-   jjjjjjjjj)    3-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-propionic    acid,-   kkkkkkkkk)    4-[2-(6-Methyl-pyridin-2-yl)-3-quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-5-yl]-benzoic    acid,-   lllllllll)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid cyclopentylamide,-   mmmmmmmmnm)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(2-morpholin-4-yl-ethyl)-amide,-   nnnnnnnnn)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid [2-(1H-imidazol-4-yl)-ethyl]-amide,-   ooooooooo)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(2-methylamino-ethyl)-amide,-   ppppppppp)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(3-methylamino-propyl)-amide,-   qqqqqqqqq)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(2-dimethylamino-ethyl)-amide,-   rrrrrrrrr)    (4-Methyl-piperazin-1-yl)-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-methanone,-   sssssssss)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid cyclobutylamide,-   ttttttttt)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid cyclopropylamide,-   uuuuuuuuu)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(1-ethyl-propyl)-amide,-   vvvvvvvvv)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid ethyl amide,-   wwwwwwwww)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid isobutyl-amide,-   xxxxxxxxx)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid tert-butylamide,-   yyyyyyyyy)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid isopropylamide,-   zzzzzzzzz)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid propylamide,-   aaaaaaaaaa)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(2-methyl-butyl)-amide,-   bbbbbbbbbb)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid((2S)-2-methyl-butyl)-amide,-   cccccccccc)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(2S)-sec-butylamide,-   dddddddddd)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(2R)-sec-butylamide,-   eeeeeeeeee)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid((1R)-1,2-dimethyl-propyl)-amide,-   ffffffffff)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(pyridin-4-ylmethyl)-amide,-   gggggggggg)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(pyridin-3-ylmethyl)-amide,-   hhhhhhhhhh)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(pyridin-2-ylmethyl)-amide,-   iiiiiiiiii)    6-(3-Quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-pyridine-2-carboxylic    acid amide,-   jjjjjjjjjj)    1-(4-Methyl-piperazin-1-yl)-2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-ethanone,-   kkkkkkkkkk)    N-(2-dimethylamino-ethyl)-2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy)-acetamide,-   llllllllll)    N-(2-dimethylamino-ethyl)-N-methyl-2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetamide,-   mmmmmmmmmm)    N,N-Dimethyl-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-benzamide,-   nnnnnnnnnn)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid amide,-   oooooooooo)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-H]pyrazol-3-yl)-quinoline-7-carboxylic    acid(2-dimethylamino-ethyl)-methyl-amide,-   pppppppppp)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-H]pyrazol-3-yl)-quinoline-7-carboxylic    acid(3-dimethylamino-propyl)-methyl-amide,-   qqqqqqqqqq)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-H]pyrazol-3-yl)-quinoline-7-carboxylic    acid dimethylamide,-   rrrrrrrrrr)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-H]pyrazol-3-yl)-quinoline-7-carboxylic    acid methylamide,-   ssssssssss)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid pyridin-2-ylamide,-   tttttttttt)    N-(2,2-Dimethylamino-ethyl)-N-methyl-3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-propionamide,-   uuuuuuuuuu)    2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-6-carboxylic    acid(2-dimethylamino-ethyl)-amide,-   vvvvvvvvvv)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-6-carboxylic    acid(3-dimethylamino-propyl)-amide,-   wwwwwwwwww)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-6-carboxylic    acid(2-morpholin-4-yl-ethyl)-amide,-   xxxxxxxxxx)    1-[2-(Quinolin-4-yl)-1-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-7-carboxylic    acid N,N-dimethylaminoethylamide,-   yyyyyyyyyy)    4-[2-(6-Methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-7-carbox-ylic    acid(2-piperidin-1-yl-ethyl)amide,-   zzzzzzzzzz)    N-(2-Dimethylamino-ethyl)-3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-propionamide,-   aaaaaaaaaaa)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic    acid(3-dimethylamino-propyl)-amide,-   bbbbbbbbbbb)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic    acid(3-pyrrolidin-1-yl-propyl)-amide,-   ccccccccccc)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic    acid(3-morpholin-4-yl-propyl)-amide,-   ddddddddddd)    3-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-propionamide,-   eeeeeeeeeee)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-6-carboxylic    acid(2-dimethylamino-ethyl)-amide,-   fffffffffff)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-6-carboxylic    acid(2-morpholin-4-yl-ethyl)-amide,-   ggggggggggg)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-6-carboxylic    acid,-   hhhhhhhhhhh)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-6-carboxylic    acid hydrazide,-   iiiiiiiiiii)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-6-carboxylic    acid amide,-   jjjjjjjjjjj)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-6-carboxylic    acid(3-methylamino-propyl)-amide,-   kkkkkkkkkkk)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-6-carboxylic    acid amide,-   lllllllllll)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-6-carboxylic    acid(2-hydroxy-ethyl)-amide,-   mmmmmmmmmmm)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid hydrazide,-   nnnnnnnnnnn)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid hydroxyamide,-   ooooooooooo)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(2-amino-ethyl)-amide,-   ppppppppppp)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(2-hydroxy-ethyl)-amide,-   qqqqqqqqqqq)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-sulfonic    acid amide,-   rrrrrrrrrrr)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b)pyrazol-3-yl)-quinoline-7-sulfonic    acid methylamide,-   sssssssssss)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-sulfonic    acid dimethylamide,-   ttttttttttt)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-sulfonic    acid(3-dimethylamino-propyl)-amide,-   uuuuuuuuuuu)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-sulfonic    acid diethylamide,-   vvvvvvvvvvv)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-sulfonic    acid(2-piperidin-1-yl-ethyl)-amide,-   wwwwwwwwwww)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-sulfonic    acid(2-hydroxy-ethyl)-amide,-   xxxxxxxxxxx)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ylamine,-   yyyyyyyyyyy)    2-Dimethylamino-N-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazo]-3-yl)-quinolin-7-yl]-acetamide,-   zzzzzzzzzzz)    3-Dimethylamino-N-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]propionamide,-   aaaaaaaaaaaa)    N-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-methanesulfonamide,-   bbbbbbbbbbbb)    N-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-acetamide,-   cccccccccccc)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(2-acetylamino-ethyl)-amide,-   dddddddddddd)    N-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-methanesulfonamide,-   eeeeeeeeeeee) 1-methyl-1H-imidazole-4-sulfonic acid    {3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amide,-   ffffffffffff)    1-(2-Dimethylamino-ethyl)-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-urea,-   gggggggggggg)    1-(3-Dimethylamino-propyl)-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-urea,-   hhhhhhhhhhhh)    1-(2-Hydroxy-ethyl)-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-urea,-   iiiiiiiiiiii)    [4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-carbamic    acid methyl ester,-   jjjjjjjjjjjj)    [4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-carbamic    acid 2-hydroxy-ethyl ester,-   kkkkkkkkkkk)    [4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-carbamic    acid 2-methoxy-ethyl ester,-   llllllllllll)    1,3-Bis-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-urea,-   mmmmmmmmmmmm) Dimethyl-carbamic acid    4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl    ester,-   nnnnnnnnnnnn)    7-Bromo-2-isopropyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   oooooooooooo)    2-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-6-yl}-propan-2-ol,-   pppppppppppp)    7-(3-Chloro-propylsulfanyl)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   qqqqqqqqqqqq)    7-Bromo-4-(4-chloro-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   rrrrrrrrrrrr)    8-Chloro-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol,-   ssssssssssss)    8-Bromo-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol,-   tttttttttttt)    3-(7-Bromo-quinolin-4-yl)-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-ol,-   uuuuuuuuuuuu)    7-Bromo-4-(4-methoxy-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   vvvvvvvvvvvv)    [3-(7-Bromo-quinolin-4-yl)-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-yl]-methyl-amine,-   wwwwwwwwwwww)    3-(7-Bromo-quinolin-4-yl)-2-pyridin-2-yl-5,6-dihydro-pyrrolo[1,2-b]pyrazol-4-one,-   xxxxxxxxxxxx)    3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-benzamide,-   yyyyyyyyyyyy)    N,N-Dimethyl-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-thiobenzamide,-   zzzzzzzzzzzz)    Dimethyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-benzyl}-amine,-   aaaaaaaaaaaaa)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl-1H-quinolin-2-one,-   bbbbbbbbbbbbb)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b)pyrazol-3-yl)-quinolin-7-ol,-   ccccccccccccc)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-ol,-   ddddddddddddd)    6-Methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol,-   eeeeeeeeeeeee)    3-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-propionic    acid methyl ester,-   fffffffffffff)    4-(6-Methyl-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   ggggggggggggg)    3-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-6-yl}-propionic    acid methyl ester,-   hhhhhhhhhhhhh)    7-Amino-4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   iiiiiiiiiiiii)    N,N-Dimethyl-3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-propionamide,-   jjjjjjjjjjjjj)    N-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-acetamide,-   kkkkkkkkkkkkk)    N-Acetyl-N-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-acetamide,-   lllllllllllll)    2-Pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]piperidin-7-ol,-   mmmmmmmmmmmmm)    7-Acetoxy-2-pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]piperidine,-   nnnnnnnnnnnnn)    Methyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine,-   ooooooooooooo)    7-(Piperidin-4-yloxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   ppppppppppppp)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic    acid(2-amino-1,1-dimethyl-ethyl)-amide,-   qqqqqqqqqqqqq)    {6-[3-(4-Fluoro-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]-pyridin-2-yl}-methanol,-   rrrrrrrrrrrrr)    [6-(3-Quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-pyridin-2-yl]-methanol,-   sssssssssssss)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-phenol,-   ttttttttttttt)    7-(1-Methyl-pyrrolidin-3-ylmethoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   uuuuuuuuuuuuu)    7-(1-Methyl-piperidin-4-ylmethoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   vvvvvvvvvvvvv)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic    acid(2-dimethylamino-1,1-dimethyl-ethyl)-amide,-   wwwwwwwwwwwww)    (S)-[3-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-methanol,-   xxxxxxxxxxxxx)    (R)-[3-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-methanol,-   yyyyyyyyyyyyy)    (S)-[3-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-acetonitrile,-   zzzzzzzzzzzzz)    (R)-[3-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-acetonitrile,-   aaaaaaaaaaaaaa)    4-(3-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-quinoline,-   bbbbbbbbbbbbbb)    4-(6-Pyridin-2-yl-2,3-dihydro-pyrazolo[5,1-b]oxazol-7-yl)-quinoline,-   cccccccccccccc)    3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-oxazolidin-2-one,-   dddddddddddddd)    1-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2b]pyrazol-3-yl)-quinolin-7-yl]-imidazolidin-2-one,-   eeeeeeeeeeeeee)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-(pyridin-4-ylmethoxy)-quinoline,-   ffffffffffffff)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-(3-pyridin-3-yl-propoxy)-quinoline,-   gggggggggggggg)    7-(4,5-Dihydro-1H-imidazol-2-yl)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   hhhhhhhhhhhhhh)    4-[5-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline    (Enantiomer A),-   iiiiiiiiiiiiii)    4-[5-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline    (Enantiomer B),-   jjjjjjjjjjjjjj)    2-Pyridin-2-yl-3-quinolin-4-yl-pyrazolo[5,1-c]morpholine,-   kkkkkkkkkkkkkk)    4-[2-(6-Vinyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   llllllllllllll)    3-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2]pyrazol-3-yl]-quinolin-6-yl}-acrylic    acid,-   mmmmmmmmmmmmmm)    7-(6-Methyl-pyridazin-3-yloxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   nnnnnnnnnnnnnn)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-[4-(4-pyrimidin-2-yl-piperazin-1-yl)-butoxy]-quinoline,-   oooooooooooooo)    7-{3-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-propoxy}-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   pppppppppppppp)    Pyridin-2-yl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine,-   qqqqqqqqqqqqqq)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic    acid(2-dimethylamino-1-methyl-ethyl)-amide,-   rrrrrrrrrrrrrr)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic    acid amide,-   ssssssssssssss)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic    acid(3-dimethylamino-propyl)-amide,-   tttttttttttttt)    4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic    acid(2-dimethylamino-ethyl)-methyl-amide,-   uuuuuuuuuuuuuu)    N,N-Dimethyl-3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-acrylamide,-   vvvvvvvvvvvvvv)    4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-1-oxide,-   wwwwwwwwwwwwww)    7-Benzyloxy-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   xxxxxxxxxxxxxx) 4-[2-(6-Chloro-6-dihydro-4H-pyrrolo    loro-pyridin-2-yl)-5 [1,2-b]pyrazol-3-yl]-quinoline,-   yyyyyyyyyyyyyy)    6-(3-Quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)pyridine-2-carboxylic    acid methyl ester,-   zzzzzzzzzzzzzz)    4-(7-Chloroquinolin-4-yl)-3-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2□b]pyrazole,-   aaaaaaaaaaaaaaa)    4-(2-Furan-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   bbbbbbbbbbbbbbb)    3-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-6-yl}-acrylic    acid methyl ester,-   ccccccccccccccc)    4-[2-(2-Methyl-thiazol-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   ddddddddddddddd)    3-(4-Fluoro-phenyl)-2-(2-methyl-thiazol-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   eeeeeeeeeeeeeee)    4-[2-(2-Methyl-2H-pyrazol-3-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   fffffffffffffff)    4-(2-Thiazol-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline,-   ggggggggggggggg)    4-[2-(1-Methyl-1H-imidazol-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   hhhhhhhhhhhhhh)    6,7-Dichloro-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,-   iiiiiiiiiiiiiii)    (S)-6-Benzyloxymethyl-3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole,-   jjjjjjjjjjjjjjj)    N,N-Dimethyl-3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-acrylamide,    and the pharmaceutically acceptable salts, esters and prodrugs    thereof.

The compounds exemplified above are merely representative of theinvention and are not limiting in any fashion.

The compounds disclosed herein can be made according to the followingschemes and examples. The examples should in no way be understood to belimiting in any way as to how the compounds may be made.

The skilled artisan will appreciate that the introduction of certainsubstituents will create asymmetry in the compounds of Formula (I). Thepresent invention contemplates all enantiomers and mixtures ofenantiomers, including racemates. It is preferred that the compounds ofthe invention containing chiral centers are single enantiomers.

The compounds of the present invention can be prepared by a variety ofprocedures, some of which are illustrated in the Schemes below. It willbe recognized by one of skill in the art that the individual steps inthe following schemes may be varied to provide the compounds of Formula(I). The particular order of steps required to produce the compounds ofFormula (I) is dependent upon the particular compound being synthesized,the starting compound, and the relative lability of the substitutedmoieties.

The Compounds of Formula (I) may be prepared from several syntheticmethods. In Scheme I, Methods A and B employ a cyclization of anappropriately substituted alkylideneamino-pyrrolidin-2-one (I), MethodA, or an appropriately substituted alkanone-alkene-hydrazide (2), MethodB. One skilled in the art would also appreciate Method C, a condensationof an appropriately substituted alkyne (3) with a substituted synthon(4) to afford compounds of Formula (I).

Step a depicts a cyclization of a compound of formula (1) or asubstituted compound of formula (2), where the R group(s) can be anygroup(s), previously defined as said for R1, R2 or R3 of Formula (I)from here on. Typically, the appropriate compound of formula (1) iscontacted to a suitable base that can form the anion of the hydrazone,such as lithium diisopropylamide, potassium bis(trimethylsilyl)amide,lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide,sodium hydride, lithium hydride, potassium hydride, sodium alkoxides(sodium hydoxide, sodium methoxide, or sodium ethoxide) or potassiumalkoxides (potassium hydroxide, potassium methoxide, potassiumt-butoxide or potassium ethoxide), with sodium hydride being thepreferred base. The reaction is carried out in a suitable solvent, suchas tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide or toluene,preferably N,N-dimethylformamide at temperatures of about 0 to 100° C.The products can be isolated and purified by techniques well known inthe art, such as precipitation, filtration, extraction, evaporation,trituration, chromatography, and recrystallization. Optionally, avariation of step b of Scheme 1, may be appropriate for the formation of4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine derivatives, when n equals to2, to give the corresponding derivatives of Formula (1) as shown inMethod B.

Another variation a skilled artisan would appreciate is Method C for theformation of Formula (I), in Scheme I, is step b, which is known andappreciated in the art (Ranganathan, Darshan; Bamezai, Shakti,Tetrahedron Lett., 1983, 1067-1070). For example, an alkyne of (3) isreacted with a compound of (4) in a suitable solvent, such astetrahydrofuran, N,N-dimethylformamide, or toluene, xylene, preferablyxylene at temperatures of about 0 to 150° C. The products can beisolated and purified by techniques described above.

Scheme II, step c, depicts an acylation of an appropriate aromaticand/or heteroaromatic compound of formula (5) and an appropriatecarbonyl ester of formula (6) to give a compound of formula (7). Thearomatic and/or heteroaromatic compounds of formula (5) are commerciallyavailable or can be produced a condensation-cyclization by the use of anappropriate substituted aryl-heteroaryl-amine of formula (8), where R″is previously described as substitutions for the R2 groups of Formula(I). For an example, methyl vinyl ketone can be reacted with formula (8)in the presence of an acid to afford aromatic-heteroaromatic-methylcompounds of formula (5). The acylation of formula (5) requires that X,of formula (6), to be a suitable leaving group, such as C1-C6 alkoxy,disubstituted amino, halo, C1-C6 thioether or arly thio, preferablydisubstituted amino. The reaction is typically carried out in thepresence of a suitable base that can create an anion of the compound offormula (5), such as lithium diisopropylamide, potassiumbis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, sodium hydride, lithium hydride, potassiumhydride, sodium alkoxides (sodium methoxide, or sodium ethoxide) orpotassium alkoxides (potassium methoxide, potassium t-butoxide orpotassium ethoxide), with potassium bis(trimethylsilyl)amide being thepreferred base. Generally, the reaction is carried out in suitablesolvents, such as tetrahydrofuran and toluene or a combination of such,at temperatures of about −78° C. to ambient temperature. The product,formula (7), can be isolated and purified by techniques well known inthe art, such as precipitation, filtration, extraction, evaporation,trituration, chromatography, and recrystallization. Another variation ofthe acylation step c, is to use a nitrile compound of formula (10) inplace of the aromatic- or heteroaromatic-methyl compounds of formula(5). The product, formula (11), can be transformed to formula (7) byhydrolysis of the nitrile group and then subsequent decarboxylation.Generally, a compound of formula (11) is dissolved in a hydrogen halideacid solution, preferably hydrogen chloride. The reaction is carried outat temperatures of about ambient to refluxing for about 24 hours. Thistype of reaction is well known and appreciated in the art (Larock, R.C., Comprehensive Organic Transformations, copyright 1989, VCH, pp 993).Compounds of formula (10) can be acquired by treatment of an appropriatesubstituted aromatic- or heteroaromatic-methyl group with a halogenatingreagent, such as N-halosuccinimides, preferably N-bromosuccinimide incarbon tetrachloride and subsequently reacting thearomatic-halomethylene intermediate with a nitrile source, such aslithium cyanide, potassium cyanide, or trimethylsilyl cyanide,preferably sodium cyanide. The reaction is carried out at ambienttemperatures for about 24 hours, as shown in step d, to afford theacetonitrile compounds of formula (10), (Larock, R. C., ComprehensiveOrganic Transformations, copyright 1989, VCH, pp 313; Eur. J. Org. Chem.1999, 2315-2321).

In Scheme II, step f, compound of formula (7) is contacted to anappropriate compound of formula (9), this type of compound is known andappreciated in the art (Taylor, Edward C.; Haley, Neil F.; Clemens,Robert J., J. Amer. Chem. Soc., 1981, 7743-7752), to give the compoundof formula (1). Typically, the reaction is carried out in an acidicsolvent, such as acetic acid and a suitable acid scavenger such aspyridine, or triethylamine. The reaction is carried out at temperaturesof about 60° C. to ambient for 4-24 hours. The products can be isolatedand purified by techniques described above.

Another variation a skilled artisan would appreciate in the formation ofFormula (1) is shown in Scheme III.

Scheme III, step g, depicts a Claisen condensation of two appropriatesubstituted carbonyl esters, where X for both compounds of formula (6)and formula (13) is a suitable leaving group as previously described,preferably a C1-C6 alkoxy group. The Claisen condensation is well knownand appreciated in the art (March, J., Advanced Organic Chemistry,copyright 1985, John Wiley and Sons, Inc., pp 437-439). The products offormula (14) can be isolated and purified by techniques described above.

In Scheme III, step f conditions can be applied to a compound of formula(14) with the appropriate compound of formula (9), to give the compoundof formula (15). Typically, the reaction is carried out in a suitablesolvent such as ethanol, N-methylpyrrolidinone or pyridine with pyridinebeing the preferred solvent. The reaction is carried out at temperaturesof about 60° C. to ambient for 4-24 hours. The products can be isolatedand purified by techniques described above.

Step c, as described above, depicts the cyclization of a compound offormula (15) to give an optionally substituted compound of formula (16).Typically, the appropriate compound of formula (15) is reacted with to asuitable base that can form the anion of the hydrazone, sodium hydridebeing the preferred base in a suitable solvent preferablyN,N-dimethylformamide at temperatures of about 0 to 100° C. Optionally,a hydrolysis of the carboxyl ester of formula (16) can be performed. Theproducts can be isolated and purified by techniques described above.

Step h depicts the transformation of a carboxylic acid, formula (16), toa halide of formula (17). This transformation is well known andappreciated in the art (Larock, R. C., Comprehensive OrganicTransformations, 2^(nd) Ed., copyright 1999, John Wiley & Sons, pp741-742). The halide of formula (17) can be used as a leaving group incombination with a substituted aryl- or heteroarylboronic acid or esterin the presence of a suitable palladium catalyst, preferablytetrakis(triphenylphosphine)palladium(0), and a suitable base such aspotassium carbonate to further give compounds of Formula (I) (Suzukireaction see: Miryaura, N.; Yanagi, T.; Suzuki, A. ThePalladium-Catalyzed Cross Coupling Reaction of Phenylboronic Acid withHaloarenes in the Presence of Bases. Synth. Commun., 1981, 513-518).

Scheme TV, step j, depicts a carbonylation reaction for the formation ofcompounds of formula (6) and (20), where X is a suitable leaving groupdescribed as above, preferably a halogen. Compounds of formula (18) and(19) are used in the formation of formula (6) and (20), respectively.The carbonyl group of formula (6) and (20) can further undergo asynthetic transformation to incorporate the leaving group X, where X ispreviously described. The Y group can be an aromatic or heteroaromatichalide and the reaction can be carried out in the presence of carbonmonoxide, a suitable nucleophile, such as an amine or an alcohol, with apalladium (0) or palladium (II) catalyst, such as1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II):dichloromethane, tetrakis(triphenylphosphine)-palladium(0),bis(triphenylphosphine)palladium (II) chloride or palladium(II) acetate,tetrakis(triphenylphosphine)palladium(0),tris-(benzylideneacetone)dipalladium(0), palladium dichloride, palladiumbis(trifluoroacetate), or preferably1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II):dichloromethane.All reagents of the reagents are combined in a suitable solvent,typically terahydrofuran, toluene or ethylene glycol dimethyl ether,stirred at temperatures of about 0 to 80° C. All products can beisolated and purified by techniques described above.

Scheme V depicts the conversion of optionally substituted heteroaryls tooptionally substituted carboxylic acid derivatives. Reaction sequencesof this type are well known and appreciated in the art (Fife, Wilmer K.,J. Org. Chem., 1983, 1375-1377). A representative example of thesereactions are as follow. For example, in step k, an optionallysubstituted pyridine compound of formula (21), where R is previouslydescribed as the substitutions for R1 or R2 of Formula (I), is treatedwith hydrogen peroxide in acetic acid, at reflux. Formula (23) isproduced from the crude intermediate, formula (22), and results from theremoval of the solvent in step k, the addition of a nitrile source,preferably trimethylsilyl cyanide along with a disubstituted carbamylhalide, such as dimethylcarbamyl chloride. The reaction is carried outat ambient temperatures for about 24 hours. All products can be isolatedand purified by techniques described above.

Scheme V, step e, the nitrile compounds of formula (23) are hydrolizedby an acid to give the carboxylic acid of formula (24). Generally, acompound of formula (23) is dissolved in a hydrogen halide acidsolution, preferably hydrogen chloride. The reaction is carried out attemperatures of about ambient to reflux for about 24 hours. This type ofreaction is well known and appreciated in the art (Larock, R. C.,Comprehensive Organic Transformations, copyright 1989, VCH, pp 993).Formula (24) can then be converted to the appropriate carbonyl leavinggroup, where X is a suitable leaving group described as above as shownin step m. This conversion is well known and appreciated in the art(Larock, R. C., Comprehensive Organic Transformations, copyright 1989,VCH, pp 966).

Alternatively, the carboxylic acid of formula (24) can be reduced to thecorresponding alcohol by borane in tetrahydrofuran and then converted toa leaving group. Theses transformations are well known and appreciatedin the art (Larock, R. C., Comprehensive Organic Transformations,copyright 1989, VCH, pp 552 reduction; pp 335 conversion to leavinggroup). The desired products may be isolated and purified by techniquesdescribed above.

Scheme VI, step o, depicts a hydrazination of formula (7) affording ahydrazone compound of formula (27). Typically the reaction is carriedout with a suitable source of hydrazine, preferably anhydrous hydrazinein an acidic solution consisting of an alcohol, such as methanol,ethanol, or propanol, and a hydrogen halo acid, preferably hydrogenchloride, is used as the solvent. The product can be isolated andpurified by techniques described above. Compounds of formula (28) arecommercially available or can be produced by a ring opening ofappropriate substituted cyclic-carbonyl esters. Step p depicts thesering openings which can be accomplished by an acid hydrolysis using suchas; hydrogen bromide with acetic acid or trimethyl aluminum can give thecorresponding carboxylic acid derivatives to be further transformed togive compound of formula (28).

Scheme VI, step c previously described, transforms the hydrazones offormula (27) to the hydrazides of formula (2), by acylation withcompounds formula (28). The compound of formula (28) can be anappropriate carboxylic acid derivative, where X can be a leaving grouppreviously described, preferably a halogen, most preferably a chloride,and where n and m can equal 1 or 2 carbons. The reaction is carried outin the presence of an acid scavenger such as pyridine or triethylamine.The reagents are combined, and products isolated and purified bytechniques described above. The conversion of amines to an amides byacylation is well known and appreciated in the art (Larock, R. C.,Comprehensive Organic Transformations, copyright 1989, VCH, pp 979).

One skilled in the art would appreciate the formation of formula (3) bythe palladium-promoted coupling reaction of an alkyne and an aromatichalide. Such a reaction is known and appreciated in the art (Reisch,Johannes; Gunaherath, G. M. Kamal B., J. Heterocycl. Chem., 1993;1057-1060, Inouye, Masahiko; Miyake, Toshiyuki; Furusyo, Masaru;Nakazumi, Hiroyuki, J. Amer. Chem. Soc., 1995; 12416-12425). Forexample, in Scheme VII, step q, an appropriate substituted alkyne offormula (29) and a variably substituted compound of formula (30), whereR′ and R″ are previously described as substitutions for R1 and R2groups, respectively, for Formula (I) and where Y can be an appropriateleaving group such as a halide and the R group(s) can be one or moregroups as previously described. Typically, the reaction is carried outby combining a compound of formula (30) with a palladium (0) orpalladium (II) catalyst as described previously, preferablybis(triphenylphosphine)palladium (II) chloride with a suitable base,such as trialkylamine or pyridine, preferably triethylamine along with acopper(I) halide to facilitate coupling to a compound of formula (29).All reagents are combined in a suitable solvent, typicallyterahydrofuran, toluene or ethylene glycol dimethyl ether, stirred attemperatures of about 0 to 80° C. All products can be isolated andpurified by techniques described above.

Scheme VIII, depicts the incorporation of a heteroatom into the acyclicring portion of Formula (I). In step r, an appropriate compound offormula (27) is reacted with an oxalic acid monoalkyl ester derivative,such as ethyl oxalyl chloride to give a compound of formula (31).Generally, the reaction is carried out in a suitable solvent, such aspyridine, at temperatures from ambient to reflux. The products can beisolated and purified by techniques described above.

The reaction of step s, a compound of formula (31) is converted to alactone of formula (32), by a sequence of reactions. An appropriatecompound of formula (31) is dissolved in a suitable solvent, such astetrahydrofuran, N,N-dimethylformamide, or toluene, preferablyN,N-dimethylformamide at temperatures of about 0 to 80° C. A suitablebase, such as sodium carbonate, sodium bicarbonate, cesium carbonate,cesium bicarbonate, lithium carbonate, potassium carbonate, preferablycesium carbonate, is used in 1-3 molar equivalence, along with anappropriate alkylating reagent, such as a halo-alcohol, preferably2-bromo-ethanol. The products can be isolated and purified by techniquesdescribed above.

Step t depicts a ring opening and reduction of a compound of formula(32) to give a di-alcohol compound of formula (33). Typically, thereaction is carried out with a suitable reducing agent, such as boranes(sodium borohydride, borane-methyl sulfide complex or potassiumborohydride), or aluminum hydrides (lithium aluminum hydride, sodiumaluminum hydride or potassium aluminum hydride, preferably lithiumaluminum hydride). All of the reagents are combined in a suitablesolvent, typically dichloromethane, chloroform, tetrahydrofuran,dioxane, or diethyl ether and are stirred from 1 to 72 hours at atemperature of from ambient to about the refluxing temperature of thesolvent. The desired product may be isolated and purified by techniquesdescribed above.

The reaction in step u depicts a ring formation of a compound of formula(33) to give a compound of formula (34), a compound derivative ofFormula (I). The di-hydroxy compound of formula (33) is mixed with asuitable base, such as sodium hydride, potassium hydride, typically atapproximately 2-4 molar equivalents of base per molar equivalent of thedi-alcohol. A suitable sulfonylating agent, such as p-toluenesulfonylchloride, p-nitro-benzenesulfonyl chloride, trifluoromethanesulfonicanhydride, or preferably methanesulfonyl chloride, is added in thereaction for the conversion of the hydroxy group of formula (33) into asuitable leaving group. The reaction is carried out in a suitablesolvent, such as dichloromethane, chloroform, tetrahydrofuran, dioxane,or diethyl ether, preferably tetrahydrofuran, and stirred for 1 to 24hours at a temperature of about 0° C. to ambient. The desired productmay be isolated and purified by techniques described above.

Scheme IX, elaborates substitution of the R1 and R2 groups of Formula(1). A representative transformation is seen in step v, a nucleophilicaddition of appropriate compounds of formula (35) and (36), where Z isan halide, such as chloro, bromo, or iodo, or a sulfonic esterderivative substituted anywhere upon the aromatic ring, can undergo anucleophilic substitution with appropriate nucleophiles, where the Rgroup(s) is described above, to give compounds of formula (37) and (38),respectively. Typically, the reaction is carried out in the presence ofC1-C6 alkoxide or variably substituted amine neat or inN,N-dimethylformamide, toluene or xylene, preferablyN,N-dimethylformamide at temperatures of about 100° C. to reflux.Alternatively, a metal-nucleophile, such as trialkylstannyls, or boraneswith a suitable base such as, sodium alkoxides (sodium methoxide, orsodium ethoxide) or potassium alkoxides (potassium methoxide, orpotassium ethoxide) can be used with a palladium catalyst, previouslydescribed, preferably tetrakis(triphenylphosphine)palladium(0). Or askilled artisan can use as the metal-nucleophile a magnesium-halogenreagent (Grignard reagent) along with the palladium catalyst, to furtherelaborate the aryl-substituents at the C3 and C4 positions of thepyrazole of Formula (1). All reagents of the reagents are combined in asuitable solvent, typically tetrahydrofuran, toluene or ethylene glycoldimethyl ether, stirred at temperatures from room temperature to reflux.All products can be isolated and purified by techniques described above.

Scheme X depicts the manipulation of hydroxy-aryl compounds of formula(40) for further alkylations and transformations to enable the scope ofthis invention, where the R group(s) are previously described.Representative conversions are shown in Scheme X.

Step w, depicts the deprotection of a protected aromatic-hydroxy groupof formula (39) to give a compound of formula (40), where the “Pg” canbe an alkoxide. The deprotection is well known and appreciated in theart (Greene T. W., Wuts, P. G. M. Protective Groups in OrganicSynthesis, copyright 1991, John Wiley and Sons, Inc., pp146-149). Theproduct of formula (40) can be isolated and purified by techniquesprevious described.

Step x, depicts the formation of an aryl ether compound of formula (40)to give the compounds of Formula (1). The formation of an aryl ether iswell known and appreciated in the art (March, J., Advanced OrganicChemistry, copyright 1985, John Wiley and Sons, Inc., pp342-343, 589 andMundy, B. P., Ellerd, M. G. Name Reactions and Reagents in OrganicSynthesis, copyright 1988, John Wiley and Sons, Inc., pp 242, 530;Sawyer, J. S., Schmittling, E. A., Palkowitz, J. A., Smith, III, W. J.,J. Org. Chem., 1998, 63, 6338-6343). The products can be isolated andpurified by techniques described above.

Step y depicts an alkyation of a compound of formula (40) to give avariably substituted compound of formula (41), where the leavinggroup(s) “Lg” and “Lg′” can include such leaving groups, but are notlimited to, halides, oxonium ions, alkyl perchlorates,ammonioalkanesulfonate esters, alkyl fluorosulfonates, nonaflates,tresylates, triflates, and sulfonic esters, preferably the mesylate ortosylate, given “Lg” and “Lg′” are not the same group. Typically, theappropriate compound of formula (40) is reacted with a suitable basethat can form the anion of the phenol, such as lithium carbonate, sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydride,lithium hydride, potassium hydride, with cesium carbonate being thepreferred base, in the presence of a compound of formula (42). Thereaction is carried out in a suitable solvent, such as tetrahydrofuran,N,N-dimethylformamide, dimethylsulfoxide, dimethyl acetamide or toluene,preferably N,N-dimethylformamide at temperatures of about 0 to 100° C.The products can be isolated and purified by techniques described above.

Step z depicts the nucleophilic substitution of leaving group “Lg”, by anucleophile to form a compound of the formula (43). Nucleophilicsubstitution is well known and appreciated in the art (March, J.,Advanced Organic Chemistry, copyright 1985, John Wiley and Sons, Inc.,pp 255-446). Typically, the compound of formula (41) is reacted with anucleophile of formula (44), which is typically, but not limited to,primary amines, secondary amines, alcohols or thiols. The reaction iscarried out in a suitable solvent, such as tetrahydrofuran,N,N-dimethylformamide, dimethylsulfoxide, dimethyl acetamide or toluene,preferably N,N-dimethylformamide at temperatures of about 0 to 100° C.The products can be isolated and purified by techniques described above.

A skilled artisan would appreciate oxidation reactions on compounds ofFormula (I) to further elaborate the scope of this invention.Representative examples are shown in Scheme XI. For example, a sulfur-or nitrogen-containing compound can be oxidized to an oxide (nitrogen orsulfur) or a bis oxide (sulfur) by oxidizing reagents. Typically, acompound of Formula (I) is contacted to an oxidant which is typically,but not limited to, hydrogen peroxide, acetoyl peroxide, benzoylperoxide, tert-butyl peroxide, ozone, Oxone®, preferably Oxone®, in thepresence of an acid which is typically, but not limited to,hydrochloric, sulfuric, nitric, phosphoric, acetic, trifluoroaceticacids, preferably acetic acid. The reaction is carried out in a suitablesolvent, such as tetrahydrofuran, water, an alcohol, such as, but notlimited to, ethanol, or methanol, preferably a mixture of water andtetrahydrofuran at temperatures of about 0 to 100° C. Oxidations arewell known and appreciated in the art (March, J., Advanced OrganicChemistry, copyright 1985, John Wiley and Sons, Inc., pp 1089-1090).

A skilled artisan would appreciate palladium catalyzed couplings toelaborate the scope of the invention as shown in Scheme XII.

Aryl substitutions of may be accomplished, through the use of a halo orsulfonyl leaving group, X, in combination with a substituted aryl- orheteroarylboronic acid or ester in the presence of a suitable palladiumcatalyst and a suitable base such as potassium carbonate as previouslydescribed in Scheme III. Another palladium catalyzed reaction,incorporates alkenyl substitutions may be realized by reacting thecorresponding aryl halide with an alkene in the presence of a suitablebase such as triethylamine, a palladium catalyst, and a suitable ligand,such as triphenylphosphine. The resulting alkene may be reduced viahydrogenation to provide a substituted alkane-linked derivative (Heckreaction see: Whitcombe, N.J.; Hii, K. K.; Gibson, S. E. Advances in theHeck chemistry of aryl bromides and chlorides, Tetrahedron, 2001,57(35), 7449-7476).

A skilled artisan would also appreciate a carbonylation using anaromatic halide along with a palladium catalyst and an atmosphere ofcarbon monoxide in a suitable solvent such as methanol as previouslydescribed in Scheme IV.

Scheme XIII also elaborates compounds of Formula (I) to further enablethe scope of this invention. A transformation of a benzylthio-aryl to asulfonamide formation is depicted in step aa. A typical reaction is thetreatment of a benzylthio-aryl with molecular chlorine in aqueous aceticacid solution and with the removal of the solvent then coupling theproduct to an appropriate substituted amine. One skilled in the artwould also appreciate the conversion of an arylhalide of Formula (I) tothe corresponding amine, shown in step bb. For example, the arylhalideis treated with benzophenone imine and a suitable base such as sodiummethoxide, sodium iso-propoxide or preferably sodium tert-butoxide alsousing a palladium catalyst as previously described, preferablybis(dibenzylideneacetone)-palladium with an appropriate ligand such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, this type of aminationtransformation is well known and appreciated in the art (Prashad, M.;Hu, B.; Lu, Y.; Draper, R.; Har, D.; Repic, O.; Blacklock, T. J., J.Org. Chem., 2000, 65, 2612-1614).

One skilled in the art would also appreciate other transformations ofhetrocyclic substitutions, as shown in Scheme XIV.

Step cc, depicts a cyclization of a hydroxyethyl-carbamic ester, to givean oxazolidinone. This type of cyclization is well known in the art(Mistunobu, O., Synthesis, 1981, 1-28).

Step dd, depicts a transformation of the aryl carboxylic ester, to a4,5-dihydro-1H-imidazole by use of a Lewis acid such astrimethylaluminum. This type of transformation is well known in the art(Neef, G.; Eder, U.; Sauer, G.; J. Org. Chem., 1981, 46, 2824-2826).

Many of the compounds of the present invention are not only inhibitorsof TGF-beta receptor kinase, but are also useful intermediates for thepreparation of additional compounds of the present invention. Forexample, ester moieties may be reduced or hydrolized to thecorresponding alcohols or carboxylic acid (Larock, R. C., ComprehensiveOrganic Transformations, 2^(nd) Ed., copyright 1999, John Wiley & Sons,pp 1959-1968). These alcohols may then be activated and displaced by anumber of nucleophiles to provide other compounds of the invention (seeLarock, Comprehensive Organic Transformations, 2^(nd) Ed., John Wiley &Sons, New York, pg. 779-780 (1999)).

Additionally, in order to substitute alcohol derivatives with acorresponding amine, the skilled artisan would appreciate that necessaryintermediates would incorporate certain appropriate leaving groups. Suchleaving groups include, but are not limited to, halides, oxonium ions,alkyl perchlorates, ammonioalkanesulfonate esters, alkylfluorosulfonates, nonaflates, tresylates, triflates, and sulfonicesters, preferably the mesylate or tosylate. Techniques for theintroduction of these groups are also well known to the skilled artisan;see, for example, March, Advanced Organic Chemistry, 5^(th) Ed., JohnWiley and Sons, New York, pg. 445-449 (2001). The skilled artisan willappreciate the secondary amine moiety can be reacted with an appropriatereagent to introduce a suitable amino protecting group “Pg”, such as aformyl group, acetyl group, or preferably a tert-butoxycarbonyl moeity.These protecting groups may be removed at any convenient point in thesynthesis of the compounds of the present invention. Methods offormation and removal of an amino-protecting group are well known in theart; see, for example, Greene and Wuts, Protective Groups in OrganicSynthesis, 3^(rd) Ed., John Wiley and Sons, New York, Chapter 7 (1999).

For example, secondary amines may be acylated, alkylated or coupled withsimple carboxylic acids or amino acids under standard conditions, in thepresence of a peptide coupling reagent, optionally in the presence of acatalyst. Suitable peptide coupling reagents includeN,N′-carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), and1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (PEPC). Polymersupported forms of EDC (Tetrahedron Letters, 34(48), 7685 (1993)) andPEPC (U.S. Pat. No. 5,792,763) have been described, and are very usefulfor the preparation of the compounds of the present invention. Suitablecatalysts for the coupling reaction include N,N-dimethyl-4-aminopyridine(DMAP). Such coupling reactions are well known and appreciated in theart (Larock, R. C., Comprehensive Organic Transformations, 2^(nd) Ed.,copyright 1999, John Wiley & Sons, pp 1941-1949). Also One skilled inthe art would appreciate the treatment of a secondary amine with aphosgene reagent, with a suitable base such as pyridine and quenchingthe reaction with an amine or an alcohol to afford the appropriate ureasand carbamates of Formula (I) (March, J., Advanced Organic Chemistry,copyright 1985, John Wiley and Sons, Inc., pp 370-371).

A skilled artisan would recognize several other transformations that canbe applied to the synthetic process for production of useful andreactive intermediates. Such transformations include but are not limitedto alkylation or acylations of the appropriate amine, O-alkylation ofthe hydroxy intermediates, or hydroxy-halogen exchange (Larock,Comprehensive Organic Transformations, 2^(nd) Ed., John Wiley & Sons,New York, pg. 689-697 (1999)).

The skilled artisan will also appreciate that not all of thesubstituents in the compounds of Formula (I) will tolerate certainreaction conditions employed to synthesize the compounds. These moietiesmay be introduced at a convenient point in the synthesis, or may beprotected and then deprotected as necessary or desired. Furthermore, theskilled artisan will appreciate that in many circumstances, the order inwhich moieties are introduced is not critical.

The skilled artisan will appreciate that the compounds of Formula (I) inMethods A, B or C may be formed into acid addition salts usingpharmaceutically acceptable acids. The formation of acid-addition saltsis well known and appreciated in the art.

The following preparations and examples further illustrate thepreparation of compounds of the present invention and should not beinterpreted in any way as to limit the scope. Those skilled in the artwill recognize that various modifications may be made while notdeparting from the spirit and scope of the invention. All publicationsmentioned in the specification are indicative of the level of thoseskilled in the art to which this invention pertains.

Preparation 1 4,5-Dihydroxy-pentanoic acid ethyl ester

A solution of ethyl pent-4-enoate (11.7 g, 91.3 mmol) in tetrahydrofuran(420 mL) and water (40 mL) is treated with osmium tetroxide (1.0 g, 4.2mmol) and 4-methylmorpholine N-oxide (32.5 mL, 50% in water) at roomtemperature and stired for 3 h, at which time no more starting materialis detectable by TLC (SiO₂, 2% methanol/dichloromethane, R_(f)=0.40).The mixture is concentrated in vacuo and the residue chromatographed onSiO₂ (2% methanol/ethyl acetate) to afford the title compound 14.37 g(96%) as a colorless oil.

¹H NMR (CDCl₃): δ 4.10 (q, J=7 Hz, 2H), 3.60-3.80 (m, 2H), 3.45 (dd,J=7, 11 Hz, 1H), 3.00 (bs, 2H), 2.45 (dd, J=1.3, 7 Hz, 2H), 1.70-1.85(m, 2H), 1.25 (t, J=7 Hz, 3H).

Preparation 2 5-(tert-Butyl-dimethyl-silyloxy)-4-hydroxy-pentanoic acidethyl ester

A solution of 4,5-dihydroxy-pentanoic acid ethyl ester, (7 g, 43.2 mmol)and 4-dimethylaminopyridine (0.2 g, 1.73 mmol) in dichloromethane (145mL) at room temperature under nitrogen is treated withtert-butyl-dimethyl-silyl chloride (7.8 g, 51.85 mmol) and triethylamine(6.9 mL, 47.52 mmol) and stirred 18 h. The mixture is diluted withdichloromethane (100 mL), washed with water (100 mL), saturated ammoniumchloride solution, and brine. The solution is filtered and concentratedin vacuo to yield the title compound, 11.85 g (99%), as a colorless oil.

¹H NMR (CDCl₃): δ 4.05 (q, J=7 Hz, 2H), 3.50-3.65 (m, 2H), 3.30-3.40 (m,1H), 2.30-2.45 (m, 3H), 1.60-1.75 (m, 2H), 1.20 (t, J=7 Hz, 3H), 0.90(s, 9H), 0.10 (s, 6H).

Preparation 3 (2-Amino-2-methyl-propyl)-carbamic acid tert-Butyl ester

Di-tert-butyl dicarbonate (2.5 g, 11.3 mmol) is added portionwise to asolution of 2-methyl-propane-1,2-diamine (3.0 g, 34.0 mmol) in1,4-dioxane (50 mL). The mixture is stirred at room temperature for 18 hconcentrated in vacuo. The residue is purified by flash chromatography(methanol/dichloromethane (5:95)) and yielded the title compound 2.47 g(40%) as a white solid.

¹H NMR (CDCl₃) δ 5.07-4.87 (m, 1H), 3.08-2.92 (m, 2H), 1.54-1.41 (m,9H), 1.09 (s, 6H).

Preparation 4 1-Benzyloxy-4-phenyl-butan-2-ol

Benzyloxy-acetaldehyde (3.0 g, 20 mmol) is dissolved in tetrahydrofuran(200 mL), cooled to −78° C. This solution is treated withphenylethylmagnesium chloride (1.0 M in tetrahydrofuran, 24 mL, 24mmol), and stirred for one hour. The mixture is allowed to warm to roomtemperature and stirred for 4 h. The mixture is treated withhydrochloric acid (1 M, 40 mL) and extracted with ethyl acetate. Thecombined organic extracts are washed with water and brine, dried oversodium sulfate, and filtered. The filtrate is concentrated in vacuo toprovide the title compound, 4.0 g (80%), as a colorless liquid.

¹H NMR (CDCl₃) δ 7.37-7.10 (m, 10H), 4.56 (s, 2H), 3.85-3.72 (m, 1H),3.5-3.41 (m, 1H), 3.39-3.29 (m, 1H), 2.9-2.6 (m, 2H), 1.8-1.67 (m, 2H).

Preparation 5 1-Benzyloxy-4-phenyl-butan-2-one

To a solution of 1-benzyloxy-4-phenyl-butan-2-ol, (8.4 g, 32.8 mmol) indichloromethane (400 mL) is added a mixture of pyridinium chlorochromate(14.1 g, 65.6 mmol) with SiO₂ (14 g) and stirred for 3 h at roomtemperature. The mixture is filtered through a pad of SiO₂ andconcentrated to provide the title compound 5.7 g (68%) as a colorlessliquid.

¹H NMR (CDCl₃) δ 7.4-7.14 (m, 10H), 4.6 (s, 2H), 4.03 (s, 2H), 2.9-2.82(m, 2H), 2.8-2.72 (m, 2H).

Preparation 6 4-Acetoxy-3-phenyl-butyric acid methyl ester

A mixture of 4-acetoxy-3-phenyl-but-2-enoic acid methyl ester, (1.0 g,4.27 mmol), 10 wt. % palladium on activated carbon (1.0 g), acetic acid(10 mL) is shaken under an atmosphere of hydrogen on a Parr® Shaker. Themixture is filtered through a pad of Celite® and rinsed with methanol.The solution is concentrated in vacuo to yield 0.93 g (92%) of the titlecompound.

¹H NMR (CDCl₃) δ 7.40-7.10 (m, 5H), 4.30-4.05 (m, 2H), 3.60 (s, 3H),3.55-3.40 (m, 1H), 2.80-2.50 (m, 2H), 2.10 (s, 3H).

Preparation 7 Acetic Acid 2-oxo-2-phenyl-ethyl ester

A solution of 2-hydroxyaceto-phenone (10 g, 73.4 mmol), pyridine (17.4g, 220.2 mmol), dichloromethane (734 mL), 3 crystals of4-dimethylaminopyridine is cooled to −78° C. To this solution is addedacetic anhydride (13.9 mL, 146.9 mmol) then warmed to room temperatureand stirred for 18 h. The mixture is washed with water (200 mL) andbrine (200 mL) then dried over sodium sulfate. The mixture is filteredand concentrated in vacuo to yield the title compound, 13 g (99%), as acolorless liquid.

¹H NMR (CDCl₃) δ 7.9-7.2 (m, 5H), 5.32 (s, 2H), 2.20 (s, 3H).

Preparation 8 4-(3-Methoxy-phenyl)-5H-furan-2-one

3-Methoxy-phenyl-boronic acid (2.16 g, 14.2 mmol) andtrifluoromethansulfonic acid 5-oxo-2,5-dihydro-furan-3-yl ester¹ (3 g,12.92 mmol) in tetrahydrofuran (110 mL) is dissolved and de-gassed for15 min. To this solution is added sodium carbonate (3.42 g, 32.3 mmol)in water (10 mL) and tetrakis-triphenylphosphine-palladium(0) (0.75 g,0.646 mmol). The reaction mixture is refluxed for 45 min, cooled to roomtemperature, diluted with ether (50 mL) and filtered through a Celite®pad. The filtrate is washed with water and brine, dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue ischromatographed on SiO₂ (3:7 ethyl acetate/hexanes) to yield the titlecompound, 1.9 g (71%), as a white crystalline solid.

¹) Grigg, R.; Kennewell, P.; Savic, V. Tetrahedron, 1994, 5489-5494.

¹H NMR (CDCl₃): δ 7.35 (m, 1H), 7.00-7.20 (m, 3H), 6.30 (s, 1H), 5.20(s, 2H), 3.80 (s, 3H).

Preparation 9 4-(4-Fluoro-phenyl)-5H-furan-2-one

A method similar to PREPARATION 7, except employing4-fluoro-phenyl-boronic acid, is used to yield the title compound as awhite crystalline solid.

¹H NMR (CDCl₃): δ 7.50-7.60 (m, 2H), 7.15-7.25 (m, 2H), 6.35 (s, 1H),5.20 (s, 2H).

Preparation 10 4-(3-Methoxy-phenyl)-dihydro-furan-2-one

To a solution of 4-(3-methoxy-phenyl)-5H-furan-2-one, (1.9 g, 10 mmol)in tetrahydrofuran (100 mL) and is added Raney nickel (7.6 g, 50%suspension in water) the mixture is stirred under hydrogen (ambientpressure) 18 h at room temperature. The mixture is filtered throughCelite® and concentrated in vacuo to yield the title compound, 1.54 g(80%), as a white crystalline solid.

¹H NMR (CDCl₃): δ 7.25 (m, 1H), 6.75-6.90 (m, 3H), 4.65 (dd, J=7.9 Hz,J=9 Hz, 1H), 4.25 (dd, J=7.9 Hz, J=9 Hz, 1H), 3.80 (s, 3H), 3.70-3.85(m, 1H), 2.90 (dd, J=8.7, 17.5 Hz, 1H), 2.65 (dd, 1H, J=8.7, 17.5 Hz).

Preparation 11 4-(4-Fluoro-phenyl)-dihydro-furan-2-one

A method similar to PREPARATION 9, except employing4-(4-fluoro-phenyl)-5H-furan-2-one, (1.4 g, 7.86 mmol), is used to yieldthe title compound, 1.38 g (97.6%), as a white crystalline solid.

¹H NMR (CDCl₃): δ 7.15-7.35 (m, 2H), 7.00-7.10 (m, 2H), 4.65 (dd, J=7.8,9 Hz, 1H), 4.20 (dd, J=7.8, 9 Hz, 1H), 3.70-3.90 (m, 1H), 2.90 (dd, J=9,17.5 Hz, 1H), 2.60 (dd, J=9, 17.5 Hz, 1H).

Preparation 12 4-Benzyl-dihydro-furan-2-one

A mixture of 3-benzoylpropionic acid (18 g, 101 mmol), potassiumcarbonate (10 g, 75 mmol), water (45 mL) and formaldehyde (36% in water,7.8 mL, 101 mmol) is stirred at room temperature for 5 days, warmed to30° C. and stirred for 3 additional days. To this mixture is addedconcentrated hydrochloric acid (10 mL) to pH 5.0, heated at 50° C. for30 min. and cooled to room temperature. The mixture is extracted withchloroform (4×200 mL) and the combined organic extracts washed withsodium carbonate (10% in water, 3×100 mL). The solution is dried withanhydrous sodium sulfate and filtered. The filtrate is concentrated invacuo to yield 4-benzoyl-dihydro-furan-2-one (12 g) as a colorlessliquid.

To a solution of 4-benzoyl-dihydro-furan-2-one (5 g) in methanol (250mL) in a Parr® reactor is added palladium chloride (0.25 g). The mixtureis shaken under hydrogen (50 PSI) for 3 h. The mixture is filteredthrough a pad of Celite® (40 g) and the filtrate concentrated. Theresidue is chromatographed on SiO₂ (10% ethyl acetate/hexanes, then 30%ethyl acetate/hexanes) to yield the title compound, (2.5 g, 34% from3-benzoylpropionic acid), as a colorless liquid.

¹H NMR (CDCl₃) δ 7.40-7.05 (m, 5H), 4.38-4.30 (m, 1H), 4.02-3.98 (m,1H), 2.98-2.70 (m, 2H), 2.68-2.55 (m, 1H), 2.38-2.25 (m, 1H).

Preparation 13 4-Phenethyl-dihydro-furan-2-one

A mixture of 3-benzyloxymethyl-5-phenyl-pent-2-enoic acid methyl ester,(3.2 g, 13.5 mmol), 10 wt. % palladium on activated carbon (3.2 g), andacetic acid (40 mL) is placed in a Parr® Shaker under hydrogen (45 PSI)and shaken 4 h. The mixture is filtered through a pad of Celite® andconcentrated in vacuo. The residue is dissolved in toluene (30 mL),treated with p-tolunesulfonic acid (0.1 g), refluxed for 2 h andconcentrated in vacuo. The residue is chromatographed on SiO₂ (10% ethylacetate/hexanes then 50% ethyl acetate/hexanes) to yield the titlecompound 1.2 g (62%) as a colorless liquid.

¹H NMR (CDCl₃) δ 7.38-7.15 (m, 5H), 4.50-4.40 (m, 1H), 4.00-3.92 (m,1H), 2.70-2.50 (m, 4H), 2.25-2.15 (m, 1H), 1.90-1.80 (m., 2H).

Preparation 14 4-Methyl-dihydro-furan-2-one

A method similar to PREPARATION 13, except employing4-methyl-5H-furan-2-one (3 g, 30.6 mmol), is used to yield the titlecompound, 3.06 g (100%) as a colorless liquid.

¹H NMR (CDCl₃) δ 4.45-4.37 (m, 1H), 3.93-3.80 (m, 1H), 2.71-2.56 (m,2H), 2.20-1.99 (m, 1H), 1.21-1.09 (m, 3H).

Preparation 15 4-Phenyl-dihydro-furan-2-one

A solution of 4-acetoxy-3-phenyl-butyric acid methyl ester, (4.5 g, 19.2mmol) in 1,4-dioxane (29 mL) and sulfuric acid (29 mL) is stirred atroom temperature for one hour then heated at 45° C. for 18 h. Volatilesolvents are evaporated and the residue is extracted with toluene. Thecombined organic extracts are extracted with water and brine, filtered,and concentrated to yield the title compound, 2.2 g (71%), as acolorless liquid.

¹H NMR (CDCl₃) δ 7.38-7.1 (m, 5H), 4.73-4.65 (m, 1H), 4.3-4.22 (m, 1H),3.85-3.7 (m, 1H), 3.0-2.9 (m, 1H), 2.75-2.55 (m, 1H).

Preparation 16 (R)-5-Benzyloxymethyl-dihydro-furan-2-one

To a solution of (R)-5-hydroxymethyl-dihydro-furan-2-one (5 g, 43.06mmol) in tetrahydrofuran (130 mL) is added sodium hydride (2.58 g, 60%oil dispersion, 64.59 mmol) and tetrabutylammonium iodide (spatula) andstirred for 30 min. To the mixture is added benzyl bromide (6.18 mL,51.67 mmol) and refluxed for 3 h. The mixture is cooled and diluted withethyl acetate (150 mL), washed with a saturated solution of ammoniumchloride (150 mL) and brine. The mixture is dried over magnesiumsulfate, filtered and concentrated in vacuo to yield the title compound,8.87 g (100%), as a pale yellow oil.

¹H NMR (CDCl₃): δ 7.25-7.40 (m, 5H), 4.63-4.72 (m, 1H), 4.56 (s, 2H),3.68 (dd, J=10.7, 4.0 Hz, 1H), 3.58 (dd, J=10.7, 4.0 Hz, 1H), 2.04-2.68(m, 4H).

Preparation 17 (S)-5-Benzyloxymethyl-dihydro-furan-2-one

A method similar to PREPARATION 16, except employing(S)-5-hydroxymethyl-dihydro-furan-2-one (4.0 g, 34 mmol), is used toyield the title compound, 7.1 g (>98%), as a colorless oil.

¹H NMR (CDCl₃): δ 7.25-7.40 (m, 5H), 4.63-4.72 (m, 1H), 4.56 (s, 2H),3.68 (dd, J=10.7, 4.0 Hz, 1H), 3.58 (dd, J=10.7, 4.0 Hz, 1H), 2.04-2.68(m, 4H).

Preparation 18 4-(5-Methoxy-tetrahydro-furan-3-yl)-benzoic acid ethylester

A solution of sodium nitrite (1.67 g, 24.2 mmol) in water (14 mL) isadded dropwise to an ice cold mixture of ethyl 4-aminobenzoate (4.0 g,24.2 mmol) and tetrafluoroboric acid (7.8 mL, 48%, 59.78 mmol) andstirred for 30 min. Methanol (28.5 mL), 2,5-dihydrofuran (3.66 mL, 48.4mmol) and palladium(II) acetate (70 mg, 0.31 mmol) are added and themixture refluxed for 30 min. The mixture is filtered through Celite® padand the filtrate diluted with dichloromethane (100 mL). The organiclayer is separated and concentrated in vacuo. The residue ischromatographed on SiO₂ (10% ethyl acetate/hexanes) to yield the titlecompound, 2.45 g (42%), as a white solid.

¹H NMR (CDCl₃): δ 7.98 (d, J=8.3 Hz, 2H), 7.27-7.39 (m, 2H), 5.18 (m,1H), 4.27-4.40 (m, 3H), 3.61-3.87 (m, 2H), 3.40 (s, 3H), 2.28-2.70 (m,1H), 1.91-2.18 (m, 1H), 1.38 (t, J=7.1 Hz, 3H).

Preparation 19 4-(4-Chloro-phenyl)-2-methoxy-tetrahydro-furan

A method similar to PREPARATION 18, except employing 4-chloroaniline(10.0 g, 78.4 mmol), is used to yield the title compound, 6.7 g (40%),as a pale yellow oil.

¹H NMR (CDCl₃): δ 7.13-7.28 (m, 4H), 5.14 (m, 1H), 4.14-4.31 (m, 1H),3.54-3.82 (m, 2H), 3.32-3.41 (m, 3H), 2.28-2.63 (m, 1H), 1.87-2.08 (m,1H).

Preparation 20 4-(5-Oxo-tetrahydro-furan-3-yl)-benzoic acid ethyl ester

To a solution of 75% 3-chloroperbenzoic acid (2.7 g, 11.76 mmol) indichloromethane (35 mL) is added magnesium sulfate (2.0 g, 16.6 mmol)and the mixture stirred for 30 min. Solids are removed by filtration andthe filtrate treated with borontrifluoride etherate (0.5 mL, 3.92 mmol)and 4-(5-methoxy-tetrahydro-furan-3-yl)-benzoic acid ethyl ester (2.45g, 9.8 mmol) in dichloromethane (5 mL). The mixture is stirred at roomtemperature 18 h, diluted with ether (200 mL) and washed with a 10%solution of sodium thiosulfite (150 mL), a saturated solution of sodiumbicarbonate (150 mL) and brine. The mixture is dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue ischromatographed on SiO₂ (elute with 20% ethyl acetate/hexanes) to yieldthe title compound, 2.2 g (96%), as an off-white solid.

¹H NMR (CDCl₃): δ 8.04 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 4.69(dd, J=9.0, 7.9 Hz, 1H), 4.26-4.42 (m, 3H), 3.82-3.95 (m, 1H), 2.96 (dd,J=17.5, 8.7 Hz, 1H), 2.68 (dd, J=17.5, 8.7 Hz, 1H), 1.39 (t, J=7.1 Hz,3H).

Preparation 21 4-(4-Chloro-phenyl)-dihydro-furan-2-one

A method similar to PREPARATION 20, except employing4-(4-chloro-phenyl)-2-methoxy-tetrahydro-furan (6.78 g, 32 mmol), isused to yield the title compound, 6.2 g (98%), as an off-white solid.

¹H NMR (CDCl₃): δ 7.34 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 4.65(dd, J=9.1, 7.8 Hz, 1H), 4.23 (dd, J=9.1, 7.8 Hz, 1H), 3.70-3.84 (m,1H), 2.92 (dd, J=17.5, 8.8 Hz, 1H), 2.63 (dd, J=17.5, 8.8 Hz, 1H).

Preparation 22 4-Hydroxy-3-(3-methoxy-phenyl)-butyric acidbenzhydrylidene-hydrazide

Trimethylaluminum (12 mL, 2 M in hexane, 24 mmol) is added dropwise to asolution of benzophenone hydrazone (1.57 g, 8 mmol) in dichloromethane(20 mL) at room temperature and under nitrogen. After the mixture isstirred for 30 min, 4-(3-methoxy-phenyl)-dihydro-furan-2-one, (1.54 g, 8mmol) in dichloromethane (5 mL) is added. The mixture is refluxed for 5h cooled to room temperature and diluted with dichloromethane (30 mL).The mixture is treated with 4 N sodium hydroxide (30 mL) and stirred onehour. The organic layer is separated, washed with brine and, dried overmagnesium sulfate. The mixture is filtered, concentrated in vacuo andchromatographed on SiO₂ (2% methanol/dichloromethane) to yield the titlecompound, 2.25 g (73%) as a pale yellow oil.

¹H NMR (CDCl₃): δ 8.35 (bs, 1H), 7.15-7.60 (m, 11H), 6.75-6.95 (m, 3H),3.80-3.90 (m, 2H), 3.80 (s, 3H), 3.45-3.6 (m, 1H), 3.15-3.40 (m, 2H),2.15 (m, 1H).

Preparation 23 3-(4-Fluoro-phenyl)-4-hydroxy-butyric acidbenzhydrylidene-hydrazide

A method similar to PREPARATION 22, except employing4-(4-fluoro-phenyl)-dihydro-furan-2-one (1.38 g, 7.67 mmol), is used toyield the title compound, 2.8 g (90%), as a white crystalline solid.

¹H NMR (CDCl₃): δ 8.30 (bs, 1H), 7.15-7.60 (m, 12H), 6.95-7.15 (m, 2H),3.75-3.95 (m, 2H), 3.40-3.60 (m, 1H), 3.20-3.35 (m, 3H).

Preparation 24 5-(tert-Butyl-dimethyl-silyloxy)-4-hydroxy-pentanoic acidbenzhydrylidene-hydrazide

A method similar to PREPARATION 22, except employing5-(tert-butyl-dimethyl-silyloxy)-4-hydroxy-pentanoic acid ethyl ester(6.41 g, 23.2 mmol), is used to yield the title compound, 6.2 g (63%),as a yellow foam.

¹H NMR (CDCl₃): δ 8.30 (bs, 1H), 7.20-7.60 (m, 10H), 3.65-3.85 (m, 2H),3.50-3.60 (m, 1H), 3.00-3.10 (m, 2H), 2.80 (d, J=4 Hz, 1H), 1.70-2.00(m, 2H), 0.90 (s, 9H), 0.10 (s, 6H).

Preparation 25 Methansulfonic acid3-(benzhydrylidene-hydrazinocarbonyl)-2-(3-methoxy-phenyl)-propyl ester

A solution of 4-hydroxy-3-(3-methoxy-phenyl)-butyric acidbenzhydrylidene-hydrazide and (1.7 g, 4.38 mmol) and4-dimethylaminopyridine (26 mg, 0.22 mmol) in pyridine (15 mL) is cooledto 0° C. treated with methanesulfonyl chloride (0.4 mL, 5.25 mmol) andstirred 18 h at room temperature. The mixture is diluted withdichloromethane (30 mL) and washed with 1 N hydrochloric acid (30 mL), asaturated solution of sodium bicarbonate and brine. The mixture is driedover magnesium sulfate, filtered, concentrated in vacuo andchromatographed on SiO₂ (2% methanol/dichloromethane) to yield the titlecompound, 1.64 g (80%), as yellow foam.

¹H NMR (CDCl₃): δ 8.35 (bs, 1H), 7.15-7.60 (m, 10H), 6.75-6.95 (m, 4H),4.50 (m, 2H), 3.80 (m, 4H), 3.20-3.40 (m, 2H), 2.85 (s, 3H).

Preparation 26 Methanesulfonic acid3-(benzhydrylidene-hydrazinocarbonyl)-2-(4-fluoro-phenyl)-propyl ester

A method similar to PREPARATION 25, except employing3-(4-fluoro-phenyl)-4-hydroxy-butyric acid benzhydrylidene-hydrazide(2.78 g, 7.4 mmol), is used to yield the title compound, 2.1 g (62%), asa yellow foam.

¹H NMR (CDCl₃): δ 8.30 (bs, 1H), 7.20-7.70 (m, 12H), 6.90-7.10 (m, 2H),4.40-4.50 (m, 2H), 3.75 (m, 1H), 3.25-3.35 (m, 2H), 2.90 (s, 3H).

Preparation 27 Methansulfonic acid3-(benzhydrylidene-hydrazinocarbonyl)-1-(tert-butyl-dimethyl-silyloxymethyl)-propylester

A method similar to PREPARATION 25, except employing5-(tert-butyl-dimethyl-silyloxy)-4-hydroxy-pentanoic acidbenzhydrylidene-hydrazide (5.55 g, 13 mmol), is used to yield the titlecompound, 6.08 g (93%), as a yellow foam.

¹H NMR (CDCl₃): δ 8.30 (bs, 1H), 7.50-7.60 (m, 5H), 7.30-7.40 (m, 5H),4.80-4.90 (m, 1H), 3.70-3.80 (m, 2H), 3.00-3.15 (m, 5H), 2.00-2.20 (m,2H), 0.90 (s, 9H), 0.10 (s, 6H).

Preparation 28 1-Amino-4-(3-methoxy-phenyl)-pyrrolidin-2-one

Concentrated hydrochloric acid (0.35 mL) is added to a suspension of1-(benzhydrylidene-amino)-4-(3-methoxy-phenyl)-pyrrolidin-2-one, (0.8 g,2.16 mmol) in water (17 mL) and refluxed for one hour. The mixture isconcentrated in vacuo and water azeotroped away using ethanol andtoluene. The residue is dissolved in methanol (5 mL) and loaded on SCXresin (5 g). The resin is washed with methanol and 2 M solution ofammonia in methanol. Appropriate fractions are concentrated to yield thetitle compound, 402 mg (92%), as a white crystalline solid.

¹H NMR (CDCl₃): δ 7.25 (t, J=8 Hz, 1H), 6.75-6.85 (m, 3H), 4.20 (bs,2H), 3.85 (m, 1H), 3.80 (s, 3H), 3.45-3.60 (m, 2H), 2.80 (dd, J=9, 17Hz, 1H), 2.50 (dd, J=9, 17 Hz, 1H).

By the previous method the following compounds are prepared (unlessotherwise specified):

Product PREP # (Chemical Name) Physical Data 29 (S)-1-Amino-5- ¹HNMR(CDCl₃): δ 7.26-7.37(m, 5H), 4.53(s, benzyloxymethyl-pyrrolidin- 2H),3.89(bs, 2H), 3.68-3.89(m, 2H), 3.46-3.54 2-one (m, 1H), 2.26-2.53(m,2H), 1.90-2.15(m, 2H) 30 4-(1-Amino-5-oxo- ¹H NMR(CDCl₃): δ 8.02(dd,J=6.7, 1.7Hz, pyrrolidin-3-yl)-benzoic acid 2H), 7.28(dd, J=6.7, 1.7Hz,2H), 4.37(t, J=7.1Hz, ethyl ester 2H), 4.14(bs, 2H), 3.93(dd, J=8.4,7.4Hz, 1H), 3.51-3.68(m, 2H), 2.87(dd, J=17.0, 9.0Hz, 1H), 2.53(dd,J=17.0, 7.8Hz, 1H), 1.39 (t, J=7.1Hz, 3H) 31 1-Amino-4,4-dimethyl- ¹HNMR(CDCl₃): δ 4.20(bs, 2H), 3.25(s, 2H), pyrrolidin-2-one 1.93(s, 2H),1.22(s, 6H) 32 (R)-1-Amino-5- ¹H NMR(CDCl₃): δ 7.26-7.37(m, 5H), 4.53(s,benzyloxymethyl-pyrrolidin- 2H), 3.89(bs, 2H), 3.68-3.89(m, 2H),3.46-3.54 2-one (m, 1H), 2.26-2.53(m, 2H), 1.90-2.15(m, 2H) 331-Amino-4-(4-chloro- ¹H NMR(CDCl₃): δ 7.31-7.41(m, 4H), 4.03(t, J=7.7Hz,phenyl)-pyrrolidin-2-one 1H), 3.72-3.88(m, 1H), 3.59(t, J=7.7Hz, 1H),2.91(dd, J=17.4, 8.9Hz, 1H), 2.57 (dd, J=17.4, 8.9Hz, 1H) 341-Amino-4-(4-fluoro- ¹H NMR(CDCl₃): δ 7.15-7.30(m, 2H), 7.00-7.10phenyl)-pyrrolidin-2-one (m, 2H), 4.20(bs, 2H), 3.80-3.95(m, 1H),3.45-3.6(m, 2H), 2.80(dd, J=9.3, 23.6Hz, 1H), 2.50(dd, J=8.4, 23.6Hz,1H). 35 1-Amino-5-hydroxymethyl- ¹H NMR(CDCl₃): δ 4.20(bs, 2H), 4.00(dd,J=2.4, pyrrolidin-2-one 12Hz, 1H), 3.65-3.80(m, 1H), 3.60(dd, J=4.4,12Hz, 1H), 3.45(s, 1H), 2.30-2.55(m, 2H), 2.00-2.15(m, 1H), 1.75-1.90(m,1H). 36 1-amino-3-methylpyrrolidin- ¹H NMR(CDCl₃) δ: 1.21(d, 1H),1.79(m, 1H), 2-one hydrochloride 2.36(m, 1H), 2.60(m, 1H), 3.93(m, 1H),7.10 (bd s, 1H) MS ES⁺ m/e 115(M + 1). 37 1-amino-3-benzylpyrrolidin- ¹HNMR(DMSO-d₆) δ: 1.66(m, 1H), 1.99(m, 2-one hydrochloride 1H), 2.62(m,1H), 2.74(m, 1H), 3.01(m, 1H), 3.39(m, 2H), 7.18-7.30(m, 5H).

Preparation 38 1-Aminopyrrolidin-2-one hydrochloride

4-Chlorobutyryl chloride (57 mL, 510 mmol) is added to a solution ofbenzophenone hydrazone (100 g, 510 mmol) and pyridine (41 mL, 510 mmol)in anhydrous dichloromethane (520 mL) under nitrogen at a rate thatmaintains a gentle reflux throughout the addition. The mixture isstirred for 0.5 h and poured into water (1 L). The layers are separatedand the organic layer washed with brine, dried (sodium sulfate),filtered, and concentrated in vacuo to yield 4-chloro-butyric acidbenzhydrylidene-hydrazide as a residue.

MS ES⁺ m/e 303.1 (M+1).

The residue is dissolved in tetrahydrofuran (1.5 L), cooled in anice-water bath, treated with portions 60% sodium hydride suspended inmineral oil (20 g, 498 mmol) and stirred for 1 h. To the mixture isadded saturated aqueous ammonium chloride solution (1 L) and ethylacetate (1 L). The layers are separated and the organic solution washedwith brine, dried (sodium sulfate), filtered and concentrated in vacuoto yield 1-(benzhydrylideneamino)pyrrolidin-2-one as a residue.

¹H NMR (CDCl₃): δ 7.58-7.62 (m, 2H), 7.39-7.46 (m, 4H), 7.29-7.36 (m,4H) 3.31 (t, J=7 Hz, 2H), 2.32 (t, J=7 Hz, 2H), 1.91 (quintet, J=7 Hz,2H); MS ES⁺ m/e 267.1 (M+1).

The residue is suspended in water (3 L), treated with concentratedhydrochloric acid (80 mL), and heated to reflux for 1.5 h. The solutionis cooled to room temperature and extracted twice with dichloromethane.The aqueous portion is concentrated in vacuo followed by azeotropicremoval of water with three portions of absolute ethanol and threeportions of toluene to yield the title compound, 56 g (81%), as a whitesolid.

¹H NMR (DMSO-d₆): δ 3.58 (t, J=7 Hz, 2H), 2.33 (t, J=7 Hz, 2H), 2.04(quintet, J=7 Hz, 2H), TOF MS ES⁺ exact mass calculated for C₄H₈N₂(P+1): m/z=100.0637. Found: 100.0641.

Preparation 39 (L)-N-Nitrosoproline

A solution of 30 g L-proline in 100 mL water and 20 mL concentratedhydrochloric acid is cooled in ice bath and treated with 25 g sodiumnitrite over 10 min. The mixture is stirred 1 h and concentrated invacuo with minimal heat. The mixture is diluted with 1 N hydrochloricacid (100 mL) and extracted with chloroform (150 mL) and dichloromethane(2×200 mL). Organic portions are combined, dried (magnesium sulfate) andconcentrated in vacuo. The residue was crystallized fromdichloromethane-hexane to yield 5.58 g (L)-N-nitrsoproline.

MS ES⁺ m/e 145 (M+1), MS ES⁻ m/e 143 (M−1).

Preparation 40 3a H-pyrrolidino[1,2-C]1,2,3-oxadiazolin-3-one

(L)-N-Nitrsoproline (1.08 g, 7 mmol) is dissolved in ether (180 mL).This solution is added to trifluoroacetic anhydride (1.5 mL) cooled inan ice bath. The mixture is stirred 6 h in ice bath, evaporated withminimum heat, and chromatographed on SiO₂ (0 to 100% ethyl acetate inhexane) to yield (0.75 g, 85%) of the title compound as an oil.

MS ES⁺ m/e 127 (M+1).

Preparation 41 1-(Benzylidene-amino)-3-methyl-pyrrolidin-2-one

To an ice-cooled solution of water (48 mL) and concentrated hydrochloricacid (20.4 mL) added, with stirring, a solution of sodium nitrite (16.5g, 240 mmol) dissolved in water (48 mL) over 20 min. The sodium nitritesolution is added to a solution of 3-methypyrrolidinone (10.11 g, 102mmol) in water (60 mL) over 30 min while cooling the reaction mixture inan ice-salt bath. The reaction mixture is stirred 3 h in an ice-saltbath and extracted with methylene chloride (2×300 mL). The organiclayers are combined, dried (magnesium sulfate), and evaporated to yield9.22 g, (71%) of the intermediate N-nitroso compound as an oil. Productformation is confirmed by TLC (5% methanol in chloroform). The crudeN-nitroso product (9.22 g, 72.0 mmol) is dissolved in glacial aceticacid (37.5 mL) and cooled in an ice bath. Zinc dust (17.5 g, 270 mmol)is added such that the reaction temperature does not exceed 21° C. Thereaction mixture is diluted with water (125 mL) after 1 h, filtered, andthe zinc salts washed with water (25 mL). Benzaldehyde (5.3 g, 50 mmol)is added to the filtrate and the mixture stirred for 2 h. The whiteprecipitate is collected by filtration and washed with water to yieldthe title compound.

MS ES⁺ m/e 203 (M+1).

Preparation 42 1-Chloromethyl-4-fluoronaphthalene

A solution of 1-fluoronaphthalene (5.5 g, 37.6 mmol), paraformaldehyde(2.5 g, 83 mmol), glacial acetic acid (3.5 mL), phosphoric acid (2 mL)and concentrated hydrochloric acid (5 mL) is heated at 85° C. for 15 h.The reaction mixture is poured into water and extracted three times withdichloromethane. The organic extracts are combined and washed with waterand brine, dried (sodium sulfate), filtered, and evaporated to yield thetitle compound, 6.53 g (98%, as a yellow solid.

¹H NMR (CDCl₃): δ 8.12-8.19 (m, 2H), 7.67 (ddd, J=8, 7, 1 Hz,1H), 7.61(ddd, J=8, 7, 1 Hz,1H), 7.46 (dd, J=8, 5 Hz, 1H), 7.09 (dd, J=10, 8 Hz,1H), 5.02 (s, 2H).

Preparation 43 2-(Benzyloxy)-1-methoxy-4-nitrobenzene

A solution of 2-methoxy-5-nitrophenol (54.3 g, 321 mmol), benzyl bromide(26.5 mL, 223 mmol,) and cesium carbonate (73 g, 223 mmol) is stirred inN,N-dimethylformamide (250 mL) for 24 h at room temperature. The mixtureis partitioned between water and ethyl acetate. The layers are separatedand the organic layer washed three times with water, once with brine,dried (sodium sulfate), filtered and evaporated to give a crude solid.The crude product is recrystallized from ethyl acetate to yield thetitle compound, 56.4 g (68%), as a white crystalline solid.

MS ES⁺ m/e 260 (M+1).

Preparation 44 3-Benzyloxy-4-methoxy-phenylamine

To a solution of 2-(benzyloxy)-1-methoxy-4-nitrobenzene (35.35 g, 136mmol) in 1:1 ethyl acetate: ethanol (640 mL) at 80° C. is added tin(II)chloride hydrate in portions over 25 minutes. The mixture is heated atthis temperature for 5 h. The mixture is allowed to cool to roomtemperature and stirred for 2 days. The mixture is poured into water (1L) and neutralized with solid sodium bicarbonate. The mixture isextracted three times with ethyl acetate. The combined organic extractsare washed with water and brine, dried (sodium sulfate), filtered andevaporated to yield the title compound as a dark brown oil.

MS ES⁺ m/e 230 (M+1).

Preparation 45 2-Bromo-5-fluoropyridine

This preparation is conducted in a manner similar to that described forthe preparation of 2-bromopyridine from 2-aminopyridine in Org. Syn.Coll. Vol. 3, p. 136, except that 2-amino-5-fluoropyridine is used toyield the title compound, 47.5 g (55%), as a red oil.

¹H NMR (CDCl₃) δ 7.3 (ddd, 1H), 7.5 (dd, 1H), 8.3 (d, 1H).

PREPARATION 46 Ethyl 5-fluoropyridine-2-carboxylate

A mixture of 2-bromo-5-fluoropyridine (5.00 g, 28.4 mmol), sodiumacetate (9.33 g, 114 mmol), and1-1′bis(diphenylphosphino)ferrocene]dichloropalladium(II):CH₂Cl₂ (0.464g, 0.57 mmol) in ethanol (80 mL) in a Parr® high pressure stainlesssteel reactor vessel is placed under an atmosphere of 50 psi carbonmonoxide and heated at 80-100° C. for 4 h. The vessel is cooled,volatiles removed in vacuo, and the residue partitioned between ethylacetate and water. The ethyl acetate extract is washed with water andbrine, dried over sodium sulfate, filtered, and evaporated to give adark solid. The residue is chromatographed on SiO₂ (10% ethylacetate/hexanes) to yield the title compound 2.8 g (58%) as a whitesolid that is recrystallized from hexanes to give white crystals: mp61-63° C.

Preparation 47 6-Methyl-pyridine-2-carboxylic acid methyl ester

To a suspension of 6-methyl-pyridine-2-carboxylic acid (10 g, 72.9 mmol)in methylene chloride (200 mL) cooled to 0° C. is added methanol (10mL), 4-dimethylaminopyridine (11.6 g, 94.8 mmol), and EDC (18.2 g, 94.8mmol). The mixture is stirred at room temperature for 6 h, washed withwater and brine, and dried over sodium sulfate. The mixture is filteredand concentrated in vacuo. The residue is chromatographed on SiO₂ (50%ethyl acetate/hexanes) to yield the title compound, 9.66 g (92%), as acolorless liquid.

¹H NMR (CDCl₃) δ 7.93-7.88 (m, 1H), 7.75-7.7 (m, 1H), 7.35-7.3 (m, 1H),4.00 (s, 3H), 2.60 (s, 3H).

Preparation 48 6-Propylpyridine-2-carboxylic acid

A solution of 6-propyl-pyridine-2-carbonitrile (9.1 g, 61.9 mmol) in 6 Nhydrochloric acid is heated at reflux for 18 h. The mixture is cooled toroom temperature and concentrated in vacuo. The residue is partitionedbetween dichloromethane and water. The aqueous portion is adjusted to pH6 with saturated aqueous sodium bicarbonate solution and extracted fivetimes with dichloromethane. The organic extracts are combined, dried(sodium sulfate), filtered, and concentrated in vacuo to yield the titlecompound, 8.32 g (81%), as a white solid.

TOF MS ES⁺ exact mass calculated for C₉H₁₂NO₂ (p+1): m/z 166.0868.Found: 166.0874.

Preparation 49 6-Isopropylpyridine-2-carboxylic acid

A method similar to PREPARATION 48, except employing6-isopropyl-pyridine-2-carbonitrile (6.35 g, 43.4 mmol), is used toyield the title compound, 6.62 g (92%), as a white solid.

TOF MS ES⁺ exact mass calculated for C₉H₁₂NO₂ (p+1): m/z=166.0868.Found: 166.0867.

Preparation 50 6-Ethylpyridine-2-carboxylic acid hydrochloride

A method similar to PREPARATION 48 is used except employing6-ethyl-pyridine-2-carbonitrile (7.94 g, 60.1 mmol) in 6 N hydrochloricacid (150 mL), heating at reflux for 18 h, cooling to room temperature,concentrating the mixture in vacuo, and co-evaporating with toluene fourtimes to yield the title compound, 12.5 g (72%), as a white solid.

TOF MS ES⁺ exact mass calculated for C₈H₁₀NO₂ (p+1): m/z 152.0712.Found: 152.0701.

Preparation 51 Methyl 3-fluorobenzoate

A solution of 3-fluorobenzoic acid (3.0 g, 21.4 mmol) in methanol (71mL) at 0° C. is treated dropwise with thionyl chloride (3.1 mL, 42.8mmol). The solution is stirred for 15 min at 0° C., 2.5 h at roomtemperature, and 2 h at 50° C. The reaction is concentrated in vacuo andthe residue dissolved in ethyl acetate (150 mL). The organic solution iswashed with saturated aqueous sodium bicarbonate (2×100 mL), brine (100mL), and dried over sodium sulfate. The solution is decanted andconcentrated to yield the title compound, 2.61 g (79%), as a clear,colorless oil.

¹H NMR (CDCl₃): δ 7.85 (m, 1H), 7.75 (m, 1H), 7.32 (m, 1H), 7.21 (m,1H), 3.85 (s, 3H).

By the previous method the following compounds are essentially prepared(unless otherwise specified):

Product PREP # (Chemical Name) Physical Data 52 Methyl 2-fluorobenzoate¹H NMR(CDCl₃): δ 7.91(m, 1H), 7.42 (m, 1H), 7.12(m, 2H), 4.32(s, 3H) 53Methyl 4-fluorobenzoate ¹H NMR(CDCl₃): δ 8.03(m, 2H), 7.05 (m, 2H),3.92(s, 3H) 54 Methyl quinoline-2-carboxylate ¹H NMR(CDCl₃): δ 8.28(m,2H), 8.10 (m, 1H), 7.93(m, 1H), 7.78(m, 1H), 7.52(m, 1H), 4.03(s, 3H) 55Methyl 4-ethylpyridine-2-carboxylate ¹H NMR(CDCl₃): δ 8.58(m, 1H), 7.95(s, 1H), 7.32(m, 1H), 3.95(s, 3H), 2.63 (m, 2H), 1.21(m, 3H) 56 Methyl1,8-naphthridine-2-carboxylate ¹H NMR(CDCl₃): δ 9.18(m, 1H), 8.22 (m,3H), 7.51(m, 1H), 3.92(s, 3H) 57 Methyl 6-chloropicolinate ¹HNMR(CDCl₃): δ 8.05(m, 1H), 7.73 (m, 1H), 7.42(m, 1H), 3.95(s, 3H) 58Methyl 4-chloropicolinate ¹H NMR(CDCl₃): (NMR shows 2 rotamers in ˜4:1ratio; data for major conformer given) δ 8.53(m, 1H), 8.06 (m, 1H),7.41(m, 1H), 3.92(s, 3H) 59 4-Fluoro-3-trifluoromethyl-benzoic ¹HNMR(CDCl₃): δ 8.30-8.50(m, 2H), acid methyl ester 7.25(m, 1H), 3.90(s,3H) 60 2-Fluoro-3-trifluoromethyl-benzoic ¹H NMR(CDCl₃): δ 8.15(t,J=5Hz, acid methyl ester 1H), 7.75(t, J=5Hz, 1H), 7.35(t, J=5Hz, 1H),3.90(s, 3H) 61 6-Propylyridine-2-carboxylic acid TOF MS ES⁺ exact masscalculated for methyl ester C₁₀H₁₄NO₂ (p + 1): m/z = 180.1025 Found:180.1030 62 6-Isopropylpyridine-2-carboxylic acid ¹H NMR(CDCl₃): δ7.69(t, J=8Hz, methoxymethylamide 1H), 7.46(br s, 1H), 7.23(d, J=8Hz,1H), 3.81(br s, 3H), 3.41(br s, 3H), 3.10(septet, J=7Hz, 1H), 1.30(d,J=7Hz, 2H) 63 6-Ethylpyridine-2-carboxylic acid ¹H NMR(CDCl₃): δ 7.67(t,J=8Hz, methoxymethylamide 1H), 7.45(br s, 1H), 7.23(d, J=8Hz, 1H),3.78(br s, 3H), 3.40(br s, 3H), 2.86(q, J=8Hz, 2H), 1.31(t, J=8Hz, 3H)65 6-methyl-pyridine-2-carboxylic acid MS ES⁺ m/e 181 (M + 1)methoxy-methyl-amide

Preparation 66 Pyrazine-2-carboxylic acid methoxy-methyl-amide

To a solution of pyrazine-2-carboxylic acid (2.0 g, 16.1 mmol) inmethylene chloride (54 mL) at 0° C. is added oxalyl chloride (7.1 mL,80.6 mmol) and N,N-dimethylformamide (0.12 mL, 1.6 mmol). The coolingbath is removed after 10 min and the reaction mixture stirred 18 h atroom temperature. The reaction mixture is concentrated in vacuo. Theresidual oil is dissolved in methylene chloride (54 mL) and treated withN,O-dimethylhydroxylamine hydrochloride (2.36 g, 24.15 mmol) andtriethylamine (11.2 mL, 80.6 mmol). The reaction mixture is stirred for3 h at room temperature and diluted with methylene chloride. Theresulting mixture is washed with water (50 mL), saturated aqueousbicarbonate (50 mL), and brine (100 mL), and concentrated in vacuo toyield the title compound, 2.35 g (88%), as a brown oil.

¹H NMR (CDCl₃): δ 8.92 (s, 1H), 8.63 (s, 1H), 8.52 (s, 1H), 3.72 (s,3H), 3.51 (s, 3H). MS (CI, methane) m/e 168 (M+1).

By the previous method the following compounds are similarly prepared(unless otherwise specified):

Product PREP # (Chemical Name) Physical Data 676-Chloro-pyridine-2-carboxylic acid ¹H NMR(CDCl₃): δ 7.75(t, J=8.00Hz,methoxy-methyl-amide 1H), 7.50-7.70(m, 1H), 7.40(d, J=8.0Hz, 1H),3.80(s, 3H), 3.38(s, 3H) 68 6-Methyl-pyridine-2-carboxylic acid ¹HNMR(CDCl₃): δ 7.67(m, 1H), 7.43 methoxy-methyl-amide (m, 1H), 7.20(m,1H), 3.75(s, 3H), 3.39(s, 3H), 2.58(s, 3H)

Preparation 69 3-Benzyloxymethyl-5-phenyl-pent-2-enoic acid methyl ester

Methyl(triphenylphosphoranylidiene)-acetate (1 eq) and1-benzyloxy-4-phenyl-butan-2-one (1 eq) are combined in toluene andrefluxed for 18 h. Additional methyl(triphenylphosphoranylidiene)-acetate is added and refluxed for another18 h. The solvent is removed in vacuo, and the residue suspended inhexanes and filtered. The filtrate is concentrated in vacuo to yield thetitle compound.

¹H NMR (CDCl₃) δ 7.4-7.1 (m, 10H), 6.08 (s, 1H), 4.5 (s, 2H), 3.9 (s,2H), 3.65 (s, 3H), 2.9-2.55 (m, 4H)

By the previous method the following compound is similarly prepared(unless otherwise specified):

Product PREP # (Chemical Name) Physical Data 70 4-Acetoxy-3-phenyl-but-¹H NMR(CDCl₃) δ 7.4-7.1 2-enoic acid methyl ester (m, 5H), 6.05-5.59(m,1H), 4.8-4.77(m, 2H), 3.6(s, 3H), 2.1(s, 3H)

Preparation 71 (4-Fluoronaphthalen-1-yl)acetonitrile

A solution of 1-chloromethyl-4-fluoronaphthalene (5.45 g, 5.66 mmol),sodium cyanide (333 mg, 6.79 mmol), and water (2 mL) inN,N-dimethylformamide (30 mL) is stirred for 8 h, then heated at 70° C.for 15 h. The mixture is cooled to room temperature and partitionedbetween saturated sodium bicarbonate solution and ethyl acetate. Theorganic portion is washed with three portions of water, one portion ofbrine, dried (sodium sulfate), filtered and evaporated. The residue ischromatographed on SiO₂ (30% ethyl acetate/hexane) to yield the titlecompound, 4.67 g (90%), as a light brown solid. ¹H NMR (CDCl₃): δ 8.19(d, J=8 Hz, 1H), 7.87 (d, J=8 Hz, 1H), 7.68 (ddd, J=8, 7, 1 Hz, 1H),7.63 (ddd, J=8, 7, 1 Hz, 1H), 7.51 (dd, J=8, 5 Hz, 1H), 7.14 (dd, J=10,8 Hz, 1H), 4.09 (s, 2H).

By the previous method the following compound is similarly prepared(unless otherwise specified):

Product PREP # (Chemical Name) Physical Data 72(4-methanesulfonyl-phenyl)- MS ES⁺ m/e 196 (M + 1) acetonitrile

Preparation 73 Quinolin-6-yl-acetonitrile

A solution of 6-methyl-quinoline (3.00 g, 20.6 mmol), N-bromosuccinimide(3.96 g, 22.0 mmol), and benzoyl peroxide (0.51 g, 2.10 mmol) in carbontetrachloride (100 mL) is stirred at reflux for 2 h. The reaction iscooled to room temperature then washed with saturated aqueous sodiumbisulfite (50 mL). The organic phase is passed through 30 g SiO₂ (2×)eluting with dichloromethane then diethyl ether. N,N-Dimethylformamide(83 mL) is added to the combined organic fractions and solvent removedunder reduced pressure leaving only the reaction mixture inN,N-dimethylformamide. To the reaction mixture in N,N-dimethylformamideis added sodium cyanide (1.22 g, 24.9 mmol) and potassium bicarbonate(2.51 g, 24.9 mmol). The reaction mixture is allowed to stir at 50° C.for 2 h. The cooled reaction mixture is poured into pH 7 buffer (75 mL)and extracted with ethyl acetate (2×100 mL). The organic layers arecombined, washed with saturated aqueous sodium chloride (100 mL), driedover solid sodium chloride, and concentrated under reduced pressure toafford an oil that is purified by normal phase flash chromatography (120g Biotage KP-Sil 40L: 10% ethyl acetate in hexanes for 5 min, 20% ethylacetate in hexanes for 20 min, 40% ethyl acetate in hexanes for 20 min,60% ethyl acetate in hexanes for 20 min, then 60-100% ethyl acetate inhexanes ramp over 20 min) to provids 645 mg (18%) of the title compound.MS ES⁺ m/e 169 (M+1).

By the previous method the following compounds are essentially prepared(unless otherwise specified):

PREP # Product Name Physical Data 74 6-Propyl-pyridine-2-carbonitrileTOF MS ES⁺ exact mass calculated for C₉H₁₀N₂ (p + 1): m/z = 146.0844Found: 146.0832. 75 6-Isopropylpyridine-2-carbonitrile TOF MS ES⁺ exactmass calculated for C₉H₁₀N₂ (p + 1): m/z = 146.0844 Found: 146.0849 766-Ethylpyridine-2-carbonitrile TOF MS ES⁺ exact mass calculated forC₈H₈N₂ (p + 1): m/z = 132.0687. Found: 132.0691.

Preparation 77 2-Ethynyl-6-methyl-pyridine

A solution of 2-bromo-6-methylpyridine (0.5 g, 2.9 mmol) and(trimethylsilyl)acetylene (0.29 g, 2.9 mmol) in triethylamine (15 mL) ispurged with argon. Copper(I) iodide (11 mg, 0.06 mmol) and (PPh₃)₂PdCl₂(42 mg, 0.06 mmol) are added and the reaction is stirred under argon atroom temperature for 2 h. The solvent is removed in vacuo and theresidue is diluted in ethyl acetate (50 mL) and water (50 mL). Theorganic is separated and washed with brine. The solvent is removed toafford a dark oil. This oil is diluted in methanol (50 mL) and treatedwith a 1 N sodium hydroxide solution (10 mL) and stirred for 3 h at roomtemperature. The aqueous is neutralized with 1 N hydrochloric acid andextracted with ethyl acetate. The solvent is removed in vacuo to afforda dark oil that is purified by SiO₂ column chromatography to yield 1.16g (24%) of the title compound as a light yellow oil.

MS ES⁺ m/e 118 (M+1).

Preparation 78 (6-Methyl-pyridin-2-yl)-propinoic acid ethyl ester

A solution of 2-ethynyl-6-methyl-pyridine (0.5 g, 4.3 mmol) intetrahydrofuran (20 mL) is cooled to −78° C. and treated with 1.6 MN-butyllithium in hexanes (2.9 mL, 4.7 mmol) and stirred for 0.5 h. Thissolution is then treated with ethyl chloroformate (2.85 mL, 30 mmol) andstirred for 3 h while the solution warms to room temperature. Thereaction is quenched with saturated ammonium chloride solution andextracted with ethyl acetate. The solvent is removed to yield 0.67 g(83%) of desired product as a light yellow oil.

MS ES⁺ m/e 190 (M+1).

Preparation 79 4-(2-(2-Pyridyl)ethynyl)quinoline

A mixture of triphenyphosphine oxide (5.56 g, 10 mmol) in1,2-dichloroethane (30 mL) is cooled in an ice bath.Trifluoromethanesulfonic anhydride (1.57 mL, 10 mmol) is added dropwiseover 15 min. To this mixture is added a solution of1-(2-pyridyl)-2-(4-quinolyl)ethan-1-one (2.5 g, 10 mmol) in1,2-dichloroethane (10 mL) and triethylamine (2.84 mL, 20 mmol). The icebath is removed and the mixture heated at reflux for 16 h. The mixtureis diluted with dichloromethane (100 mL) and washed with water (3×100mL), dried (magnesium sulfate), filtered, concentrated in vacuo, andchromatographed on SiO₂ (0 to 100% hexane in ethyl acetate) to yield 1 gof title compound as an oil.

MS ES⁺ m/e 231 (M+1).

Preparation 80 4-Pyridin-2-ylethynyl-quinoline-2-carboxylic acid ethylester

A mixture of ethyl 4-bromoquinoline-2-carboxylate (2.80 g, 10.0 mmol, J.Org. Chem. 1947, 12, 456), triethylamine (1.7 mL, 12 mmol),bis(triphenylphosphine)-palladium(II)chloride (0.561 g, 0.80 mmol), CuI(0.114 g, 0.60 mmol), and 2-ethynylpyridine (1.11 g, 10.8 mmol) in CH₃CN(80 mL) is heated at 75-80° C. for 18 h in a sealed tube. Additionaltriethylamine (0.85 ml, 6.1 mmol), bis(triphenylphosphine)palladium (II)chloride (0.23 g, 0.40 mmol), and CuI (0.055 g, 0.29 mmol) is added andthe mixture heated for an additional 18 h. The mixture is concentratedin vacuo and partitioned between water and chloroform. The chloroformextracts are washed with brine and evaporated. The residue ischromatographed on SiO₂ (50% ethyl acetate/hexanes) to yield 1.52 g(50%) of a yellow solid. Precipitation from ethyl acetate gave the titlecompound as yellow crystals: mp 129-131° C.; MS ES⁺ m/e 303 (M+1).

Preparation 81 3-Benzyl-4-bromo-butyric acid

A mixture of 4-benzyl-dihydrofuran-2-one (1.0 g, 5.6 mmol), acetic acid(1.7 mL), HBr (33% in acetic acid, 2.0 mL) is heated at 80° C. for 4 h.The mixture is cooled to room temperature, poured into ice-water (20mL), and extracted with chloroform (2×30 mL). The combined organicextracts are washed with water and brine, dried with anhydrous sodiumsulfate, filtered, and concentrated in vacuo to yield3-benzyl-4-bromo-butyric acid, 1.5 g (99%), as a colorless liquid.

¹H NMR (CDCl₃) δ 7.30-7.12 (m, 5H), 3.58-3.35 (m, 2H), 2.80-2.38 (m,5H).

By the previous method the following compounds are prepared (unlessotherwise specified):

PREP # Product Physical Data 82 3-Bromomethyl-5-phenyl- ¹H NMR(CDCl₃) δ7.40-7.20(m, 5H), 3.70-3.65 pentanoic acid (m, 2H), 2.85-2.50(m, 4H),2.40-2.30(m, 1H), 1.90-1.70(m, 2H) 83 4-Bromo-3-phenyl-butyric ¹HNMR(CDCl₃) δ 11.3-10.5(br s, 1H), 7.4-7.2 acid (m, 5H), 3.7-3.42(m, 3H),3.1-2.98(m, 1H), 2.8-2.68 (m, 1H) 84 4-Bromo-3-methyl-butyric ¹HNMR(CDCl₃) δ 3.55-3.33(m, 2H), 2.69-2.55 acid (m, 1H), 2.41-2.21(m, 2H),1.17-1.02(m, 3H)

Preparation 85 3-Benzyl-4-bromo-butyric acid(1-pyridin-2-yl-2-quinolin-4-yl-ethylidene)-hydrazide

A mixture of 3-benzyl-4-bromo-butyric acid (2.0 g, 7.78 mmol) andthionyl chloride (6.0 mmol) is heated to 80° C. for 2 h. The thionylchloride is evaporated to yield 3-benzyl-4-bromo-butyryl chloride 2.1 g(99%), as a colorless liquid.

¹H NMR (CDCl₃) δ 7.25-7.11 (m, 5H), 3.55-3.48 (m, 1H), 3.40-3.35 (m,1H), 3.20-3.10 (m, 1H), 3.00-2.90 (m, 1H), 2.80-2.70 (m, 2H), 2.60-2.57(m, 1H).

A solution of (1-pyridin-2-yl-2-quinolin-4-yl-ethylidene)-hydrazine(2.25 g, 8.40 mmol) in anhydrous dichloromethane (100 mL) and pyridine(1.81 mL, 22.4 mmol) is cooled to −78° C., treated with a solution of3-benzyl-4-bromo-butyryl chloride (2.1 g, 7.8 mmol) in dichloromethane(10 mL), and stirred for 2 h. The mixture is treated with methanol (3mL), stirred for 10 min, and diluted with saturated ammonium chloridesolution (30 mL). The mixture is diluted with dichloromethane (300 mL),washed with water (2×50 mL) and brine (50 mL), dried with anhydroussodium sulfate, filtered, and concentrated in vacuo. The residue isprecipitated from ether to yield the title compound, 2.3 g (60%), as apale yellowish solid.

¹H NMR (CDCl₃) δ 8.88-8.82 (m, 1H), 8.68-8.60 (m, 2H), 8.30-8.15 (m,2H), 7.80-7.65 (m, 2H), 7.40-7.20 (m, 7H), 7.00-6.92 (m, 1H), 4.85 (s,2H), 3.60-3.40 (m, 2H), 3.18-3.05 (m, 1H), 2.98-2.80 (m, 3H), 2.70-2.60(m, 1H).

By the previous method the following compounds are prepared (unlessotherwise specified):

Product PREP # (Chemical Name) Physical Data  863-Benzyl-4-bromo-butyric ¹H NMR(CDCl₃) δ 8.70-8.65(m, 1H), 8.50-8.55acid(1-pyridin-2-yl-2- (m, 1H), 8.30-8.12(m, 3H), 7.88-7.60(m, 4H),quinolin-4-yl-ethylidene)- 7.30-7.10(m, 5H), 6.95-6.90(m, 1H), 4.82(s,2H), hydrazide 3.70-3.50(m, 2H), 3.20-3.05(m, 1H), 2.90-2.10 (m, 6H)  874-Bromo-3-phenyl-butyric ¹H NMR(CDCl₃) δ 8.75-8.61(m, 2H), 2.27-8.0(m,acid(1-pyridin-2-yl-2- 2H), 7.8-7.6(m, 2H), 7.53-7.45(m, 2H), 7.2-7.1quinolin-4-yl-ethyldiene)- (m, 6H), 6.88-6.8(m, 1H), 5.25-5.2(m, 1H),4.78-4.7 hydrazide (m, 1H), 3.4-3.33(m, 1H), 3.15-3.05(m, 1H),2.7-2.48(m, 2H), 2.4-2.3(m, 1H)  88 4-Chloro-butyric acid [2- ¹HNMR(CDCl₃) δ 8.82-8.86(m, 1H), 8.12-8.18 quinolin-4-yl-1-(3- (m, 1H),7.81-7.60(m, 3H), 7.36-7.46(m, 2H), trifluoromethyl-phenyl)-7.20-7.40(m, 3H), 4.3-4.38(m, 2H), 2.60-2.86(m, ethylidene]-hydrazide4H)  89 4-Chloro-butyric acid [2- ¹H NMR(CDCl₃) δ 9.10-9.00(s, 1H),9.80-9.70 quinolin-4-yl-1-(4- (m, 1H), 8.22-8.00(m, 2H), 7.85-7.55(m,6H), trifluoromethyl-phenyl)- 6.90-6.80(m, 1H), 4.50(s, 2H),3.60-3.50(m, 2H), ethylidene]-hydrazide 2.02-1.90(m, 2H)  905-Chloro-pentanoic acid ¹H NMR(CDCl₃) δ 8.75-8.70(s, 1H), 8.30-8.05[2-quinolin-4-yl-1-(3- (m, 2H), 7.98-7.60(m, 6H), 6.95-6.90(m, 1H),trifluoromethyl-phenyl)- 4.50(s, 2H), 3.60-3.50(m, 2H), 2.85-2.75(m,2H), ethylidene]-hydrazide 2.00-1.70(m, 4H)  91 5-Chloro-pentanoic acid¹H NMR(CDCl₃) δ 8.75-8.70(s, 1H), 8.20-7.95 [2-quinolin-4-yl-1-(4- (m,3H), 7.80-7.40(m, 4H), 7.15-7.05(m, 1H), trifluoromethyl-phenyl)-6.90-6.80(m, 1H), 4.50(s, 2H), 3.60-3.50(m, 2H), ethylidene]-hydrazide2.85-2.75(m, 2H), 2.00-1.70(m, 4H)  92 5-Chloro-pentanoic ¹H NMR(CDCl₃)δ 8.9-8.7(m, 1H), 8.25-8.0(m, acid[1-(4-chloro-phenyl)- 3H), 7.85-7.5(m,4H), 7.34-7.15(m, 1H), 6.97-6.87 2-quinolin-4-yl- (m, 1H), 4.4(s, 2H),3.63-3.4(m, 2H), 2.8-2.7(m, ethylidene]-hydrazide 2H), 3.37-2.3(m, 2H),1.9-1.5(m, 2H)  93 5-Chloro-pentanoic ¹H NMR(CDCl₃) δ 8.9-8.7(m, 1H),8.25-8.1(m, acid[1-(3-chloro-phenyl)- 1H), 8.05-7.95(m, 2H),7.82-7.65(m, 2H), 7.5-7.45 2-quinolin-4-yl- (m, 1H), 7.35-7.2(m, 2H),6.9-6.85(m, 1H), 4.45 ethylidene]-hydrazide (s, 2H), 3.7(s, 1H),3.6-3.4(m, 2H), 2.8-2.7(m, 2H), 2.37-2.3(m, 2H), 1.9-1.5(m, 2H)  944-Chloro-butyric acid [1- ¹H NMR(CDCl₃) δ 9.15-9.05(s, 1H), 8.80-8.70(3-fluoro-5- (m, 1H), 8.26-8.20(m, 1H), 8.10-8.05(m, 1H),trifluoromethyl-phenyl)-2- 7.85-7.60(m, 4H), 7.40-7.30(m, 1H), 6.90-6.85quinolin-4-yl-ethylidene]- (m, 1H), 4.50(s, 2H), 3.60-3.50(m, 2H),2.02-1.90 hydrazide (m, 2H)  95 5-Chloro-pentanoic acid ¹H NMR(CDCl₃) δ8.75-8.70(s, 1H), 8.30-8.05 [2-quinolin-4-yl-1-(3- (m, 2H), 7.98-7.60(m,6H), 6.95-6.90(m, 1H), fluoro-5-trifluoromethyl- 4.50(s, 2H),3.60-3.50(m, 2H), 2.85-2.75(m, 2H), phenyl)-ethylidene]- 2.00-1.70(m,4H) hydrazide  96 5-Chloro-pentanoic acid ¹H NMR(CDCl₃) δ 8.80-8.70(m,1H), 8.25-8.05 (1-phenyl-2-quinolin-4-yl- (m, 2H), 7.95-7.65(m, 4H),7.45-7.40(m, 3H), ethylidene)-hydrazide 7.00-6.90(m, 1H), 4.50(s, 2H),3.60-3.50(m, 2H), 2.0-1.80(m, 4H)  97 4-Chloro-butyric acid(1- ¹HNMR(CDCl₃) δ 8.80-8.75(m, 1H), 8.15-7.95 phenyl-2-quinolin-4-yl- (m,2H), 7.80-7.50(m, 4H), 7.40-7.10(m, 4H), ethylidene)-hydrazide 4.60(s,2H), 3.35-3.25(m, 2H), 2.30-2.20(m, 2H), 1.70-1.55(m, 2H)  985-Chloro-pentanoic acid ¹H NMR(CDCl₃) δ 9.2-9.12(m, 1H), 9.0-8.9(m,(2-[1,10]phenanthrolin-4- 2H), 8.45-8.38(m, 1H), 8.3-8.1(m, 3H), 7.9-7.6yl-1-pyridin-2-yl- (m, 3H), 7.3-7.2(m, 1H), 7.1-7.03(m, 1H), 3.6-3.45ethylidene)-hydrazide (m, 2H), 2.5-2.43(m, 2H), 1.9-1.63(m, 4H)  994-Chloro-butyric acid [2- ¹H NMR(CDCl₃) δ 8.90-8.80(s, 1H), 8.55-8.50(2-chloro-quinolin-4-yl)-1- (m, 1H), 8.30-8.10(m, 3H), 7.90-7.65(m, 3H),pyridin-2-yl-ethylidene]- 7.40-7.30(m, 1H), 6.85(s, 1H), 4.70(s, 2H),3.70-3.60 hydrazide (m, 2H), 3.10-3.00(m, 2H), 2.15-2.00(m, 2H) 1004-Chloro-butyric acid [2- ¹H NMR(CDCl₃ ) δ 8.70-8.65(m, 1H), 7.97-7.9(m,(6,8-dimethoxy-quinolin- 1H), 7.75-7.60(m, 2H), 7.30-7.23(m, 1H),7.20-7.13 4-yl)-1-(6-methyl-pyridin- (m, 1H), 6.77-6.67(m, 1H), 4.70(s,2H), 3.82 2-yl)-ethylidene]- (s, 3H), 3.7(s, 3H), 3.65-3.55(m, 2H),2.6-2.45(m, hydrazide 5H), 2.18-1.98(m, 2H) 101 4-Chloro-butyric acid[1- ¹H NMR(CDCl₃) δ 9.20-9.0(br, 1H), 8.80-8.75(6-bromo-pyridin-2-yl)-2- (m, 1H), 8.22-8.10(m, 2H), 7.80-7.55(m, 3H),quinolin-4-yl-ethylidene]- 7.45-7.40(m, 1H), 7.31-7.26(m, 1H), 6.95-6.90hydrazide (m, 1H), 4.75(s, 2H), 3.65-3.45(m, 2H), 3.00-2.90 (m, 2H),2.10-2.00(m, 2H) 102 4-Chloro-butyric acid [2- ¹H NMR(CDCl₃) δ 8.80(s,1H), 8.65-8.50(m, (6,8-dimethoxy-quinolin- 2H), 7.8-7.7(m, 1H),7.35-7.2(m, 2H), 7.0-6.93 4-yl)-1-pyridin-2-yl- (m, 1H), 6.8-6.7(m, 1H),4.70(s, 2H), 3.82(s, 3H), ethylidene]-hydrazide 3.7(s, 3H), 3.65-3.55(m,2H), 2.55-2.45(m, 2H), 2.18-1.98(m, 2H) 103 5-Chloro-pentanoic acid ¹HNMR(CDCl₃) δ 8.95-8.88(m, 1H), 8.60-8.55 [1-(6-methyl-pyridin-2- (m,1H), 8.38-8.30(m, 1H), 8.2-8.12(m, 1H), 8.0-7.90 yl)-2-quinolin-4-yl-(m, 1H), 7.87-7.80(m, 2H), 7.36-7.30(m, ethylidene]-hydrazide 1H),7.17-7.08(m, 1H), 5.0(s, 2H), 3.80-3.72(m, 2H), 3.07-2.99(m, 2H),2.63(s, 3H), 2.10-1.99(m, 4H) 104 4-Chloro-butyric acid [1- MS APCI⁺ m/e384 (M + 1) (3-fluoro-phenyl)-2- quinolin-4-yl-ethylidene]- hydrazide105 4-Chloro-butyric acid [1- MS APCI⁺ m/e 384 (M + 1)(2-fluoro-phenyl)-2- quinolin-4-yl-ethylidene]- hydrazide 1064-Chloro-butyric acid [1- MS APCI⁺ m/e 384 (M + 1) (4-fluoro-phenyl)-2-quinolin-4-yl-ethylidene]- hydrazide 107 4-Chloro-butyric acid [2- MSAPCI⁺ m/e 450 (M + 1) quinolin-4-yl-1-(3- trifluoromethoxy-phenyl)-ethylidene]-hydrazide 108 5-Chloro-pentanoic acid MS APCI⁺ m/e 398(M + 1) [1-(4-fluoro-phenyl)-2- quinolin-4-yl-ethylidene]- hydrazide 1095-Chloro-pentanoic acid MS APCI⁺ m/e 464 (M + 1) [2-quinolin-4-yl-1-(3-trifluoromethoxy-phenyl)- ethylidene]-hydrazide 110 5-Chloro-pentanoicacid MS APCI⁺ m/e 398 (M + 1) [1-(2-fluoro-phenyl)-2-quinolin-4-yl-ethylidene]- hydrazide 111 5-Chloro-pentanoic acid MSAPCI⁺ m/e 431 (M + 1) (2-quinolin-4-yl-1- quinolin-2-yl-ethylidene)-hydrazide 112 5-Chloro-pentanoic acid MS APCI⁺ m/e 409 (M + 1)[1-(4-ethyl-pyridin-2-yl)- 2-quinolin-4-yl- ethylidene]-hydrazide 1134-Chloro-butyric acid(2- MS APCI⁺ m/e 417 (M + 1)quinolin-4-yl-1-quinolin- 2-yl-ethylidene)-hydrazide 1145-Chloro-pentanoic acid MS APCI⁺ m/e 432 (M + 1)(1-[1,8]naphthyridin-2-yl- 2-quinolin-4-yl- ethylidene)-hydrazide 1154-(4-Pyridin-2-yl-3- MS APCI⁺ m/e 373 (M + 1) quinolin-4-yl-1H-pyrrol-2-yl)-butyric acid methyl ester 116 4-Chloro-butyric acid [1- MS APCI⁺ m/e402 (M + 1) (6-chloro-pyridin-2-yl)-2- quinolin-4-yl-ethylidene]-hydrazide 117 4-Chloro-butyric acid [1- MS APCI⁺ m/e 401 (M + 1)(4-chloro-pyridin-2-yl)-2- quinolin-4-yl-ethylidene] hydrazide 1184-Chloro-butyric acid ¹H NMR(CDCl₃): δ 2.20(q, J=9Hz, 2H), 3.00(t,benzhydrylidene- J=9Hz, 2H), 3.70(t, J=9Hz, 2H), 7.20(m, 2H), hydrazide7.40(m, 2H), 7.50(m, 6H), 8.50(bs, 1H) 119 4-Chloro-butyric acid [1- ¹HNMR(CDCl₃): δ 8.80(m, 1H), 8.00-8.20(m, (2-fluoro-3- 1H), 7.50-7.82(m,3H), 6.80-7.40(m, 5H), 4.60(s, trifluoromethyl-phenyl)-2- 2H),3.45-3.75(m, 2H), 2.80(m, 2H), 2.00-2.20 quinolin-4-yl-ethylidene]- (m,2H) hydrazide 120 N-[1-Aza-2-(6-methyl- MS ES⁺ m/e 381 (M + 1), and MSES⁻ m/e 379 (M − 1) pyridyl-2-yl)-3-(4- quinolyl)prop-1-enyl]-4-chlorobutanamide 121 1-[2-(6,7-Dimethoxy- MS ES⁺ m/e 405 (M + 1)quinolin-4-yl)-1-(6- methyl-pyridin-2-yl)- ethylideneamino]-pyrrolidin-2-one 122 (1-Pyrazin-2-yl-2- MS APCI⁺ m/e 264 (M + 1)quinolin-4-yl-ethylidene)- hydrazine 123 4-Bromo-butyric acid(1- MSAPCI⁺ m/e 412/414 (M + 1) pyrazin-2-yl-2-quinolin-4-yl-ethylidene)-hydrazide 124 4-Bromo-3-methyl-butyric ¹H NMR(CDCl₃) δ9.21(s, 1H), 8.73-8.70(m, acid(1-pyridin-2-yl-2- 1H), 8.52-8.47(m, 1H),8.27-8.11(m, 3H), 7.80-7.62 quinolin-4-yl-ethylidene)- (m, 3H),7.31-7.27(m, 1H), 6.92-6.87(m, hydrazide 1H), 4.82(s, 2H), 3.41-3.32(m,2H), 2.98-2.85(m, 1H), 2.67-2.52(m, 1H), 2.28-2.12(m, 1H), 1.04-0.98 (m,3H) 125 (R)-5-Benzyloxy-4- ¹H NMR(CDCl₃): δ 8.40(s, 1H), 7.45-7.55(m,hydroxy-pentanoic acid 5H), 7.20-7.40(m, 10H), 4.55(s, 2H), 3.90-4.00benzhydrylidene- (m, 1H), 3.55(dd, J=9.5, 3.9Hz, 1H), 3.45(dd, J=9.5,hydrazide 7.2Hz, 1H), 3.00-3.10(m, 2H), 2.95(d, J=3.7Hz, 1H),1.90-2.05(m, 2H) 126 4-[2-(Benzhydrylidene- ¹H NMR(CDCl₃): δ 8.36(bs,1H), 8.02(d, J=8.3Hz, hydrazinocarbonyl)-1- 2H), 7.18-7.54(m, 12H),4.36(q, J=7.1Hz, hydroxymethyl-ethyl]- 2H), 3.85-3.95(m, 2H),3.55-3.65(m, 1H), 3.24-3.38 benzoic acid ethyl ester (m, 2H), 2.18(m,1H), 1.38(t, J=7.1Hz, 3H) 127 4-Hydroxy-3,3-dimethyl- ¹H NMR(CDCl₃): δ8.44(bs, 1H), 7.22-7.58(m, butyric acid 10H), 3.42(s, 1H), 2.89(s, 2H),1.56(s, 2H), 1.09 benzhydrylidene- (s, 6H). hydrazide 128(S)-5-Benzyloxy-4- ¹H NMR(CDCl₃): δ 8.40(s, 1H), 7.45-7.55(m,hydroxy-pentanoic acid 5H), 7.20-7.40(m, 10H), 4.55(s, 2H), 3.90-4.00benzhydrylidene- (m, 1H), 3.55(dd, J=9.5, 3.9Hz, 1H), 3.45(dd, J=9.5,hydrazide 7.2Hz, 1H), 3.00-3.10(m, 2H), 2.95(d, J=3.7Hz, 1H),1.90-2.05(m, 2H) 129 3-(4-Chloro-phenyl)-4- ¹H NMR(CDCl₃): δ 8.35(bs,1H), 7.17-7.55(m, hydroxy-butyric acid 14H), 3.86(m, 2H), 3.48(m, 1H),3.18-3.38(m, benzhydrylidene- 2H) hydrazide

Preparation 130 7-Methyl-4-methyl-quinoline

A solution of 3-methyl-phenylamine (1 eq), in 1,4-dioxane is stirred andcooled to approximately 12° C. Sulfuric acid (2 eq.) is slowly added andheated at reflux. Methylvinyl ketone (1.5 eq) is added dropwise into therefluxing solution. The solution is heated for 1 h after addition iscomplete. The reaction solution is evaporated to dryness and dissolvedin methylene chloride. The solution is adjusted to pH 8 with 1 M sodiumcarbonate and extracted with three times with water. The residue ischromatographed on SiO₂ (70/30 hexane/ethylacetate) to yield the titlecompound.

MS ES⁺ m/e=158.2 (M+1).

By the previous method of the following compounds are prepared (unlessotherwise specified):

PREP # Product Name Physical Data 131 7-Ethoxy-4-methyl-quinoline TOF MSES⁺ exact mass calculated for C₁₂H₁₄NO (p + 1): m/z = 188.1075 Found:188.1059 132 6,7-Dimethoxy-4-methyl- TOF MS ES⁺ exact mass calculatedfor quinoline C₁₂H₁₄NO₂ (p + 1): m/z = 204.1025 Found: 204.1010 1336-Ethoxy-4-methyl-quinoline TOF MS ES⁺ exact mass calculated forC₁₂H₁₄NO (p + 1): m/z = 188.1075. Found: 188.1079 1346,7-Dichloro-4-methyl- MS ES⁺ m/e quinoline 212 (M + 1) 1356,7-Difluoro-4-methyl- MS ES⁺ m/e quinoline 178 (M + 1) 1364-Methyl-quinolin-6- MS ES⁺ m/e ylamine 159 (M + 1) 1377-Methoxy-4-methyl- MS ES⁺ m/e quinoline 174 (M + 1) 1387-Fluoro-4-methyl-quinoline MS ES⁺ m/e 162 (M + 1) 1398-Methoxy-4-methyl- MS ES⁺ m/e quinoline 174 (M + 1) 1408-Ethoxy-4-methyl-quinoline MS ES⁺ m/e 188 (M + 1) 1414,7-Dimethyl-quinoline MS ES⁺ m/e 158 (M + 1) 1426-Bromo-4-methyl-quinoline ¹H NMR(CDCl₃) δ 8.78-8.75(m, 1H), 8.16-8.11(m, 1H), 7.99-7.91(m, 1H), 7.81-7.72(m, 1H), 7.28-7.19(m, 1H), 2.67(s,3H) 143 8-Fluoro-4-methyl-quinoline ¹H NMR(CDCl₃) δ 8.80-8.75(m, 1H),7.85-7.80 (m, 3H), 7.60-7.30(m, 3H), 3.70(s, 3H) 144 7-Bromo-4-methyl-¹H NMR(CDCl₃) δ 8.80-8.75(m, 1H), 8.30(s, quinoline 1H), 7.90-7.85(m,1H), 7.70-7.65(m, 1H), 7.25-7.20 (m, 1H), 2.65(s, 3H) 1456-Trifluoromethoxy-4- ¹H NMR(CDCl₃) δ 8.81(m, 1H), 8.16(m, 1H),methyl-quinoline 7.80(br s, 1H), 7.58(m, 1H), 7.30(m, 1H), 2.70 (s, 3H)146 6-Trifluoromethyl-4-methyl- ¹H NMR(CDCl₃) δ 8.80-8.75(m, 1H),8.15-8.10 quinoline (m, 1H), 7.80(s, 1H), 7.60-7.55(m, 1H), 7.30-7.27(m, 1H), 2.70(s, 3H) 147 7-Methoxy-4-methyl- ¹H NMR(CDCl₃) δ8.80-8.75(m, 1H), 7.90-7.85 quinoline (m, 1H), 7.40(s, 1H), 7.22-7.18(m,1H), 7.10-7.08 (m, 1H), 4.00(s, 3H), 2.70(s, 3H)

Preparation 148 1-(2-Pyridyl)-2-(4-quinolyl)ethan-1-one

In a 3-neck 3-liter round bottom flask equipped with two additionfunnels is dissolved lepidine (10.0 mL, 75.63 mmol) in tetrahydrofuran(200 mL). One addition funnel is charged with ethyl picolinate (20.43mL, 151.26 mmol) and the other with 0.5 M potassiumbis(trimethylsilyl)amide (166.4 mL, 83.19 mmol) in toluene. The solutionis cooled to −78° C. and the base added to the reaction mixture dropwiseover 40 min. The reaction mixture is stirred an additional 1.5 h andethyl picolinate is added rapidly. The ice bath is removed and thereaction mixture stirred at ambient temperature for 3 h. The reaction isquenched with water (20 mL) and after 5 min formic acid added until thepH is slightly less than 7. The mixture is concentrated in vacuo andpartitioned between ethyl acetate (300 mL) and brine-sodium bicarbonate(300 mL) mixture. The organic layer is washed with brine and sodiumbicarbonate, dried over sodium sulfate, and concentrated. The product ischromatographed on SiO₂ (27-30% acetone in hexane) to yield 15.31 g(82%) of a yellow-brown solid.

MS ES⁺ m/e 249 (M+1).

By the previous method the following compounds are prepared (unlessotherwise specified):

Product PREP # (Chemical Name) Physical Data 1491-pyridin-2-yl-2-quinolin-4-yl- ethanone 1502-Quinolin-4-yl-1(3-trifluoromethyl- ¹H NMR(CDCl₃) δ 8.8(m, 1H), 8.3(s,phenyl)-ethanone 1H), 8.12-8.28(m, 2H), 7.80-7.90(m, 2H), 7.59-7.78(m,3H), 7.21-7.29(m, 1H), 4.80(s, 2H) 1522-Quinolin-4-yl-1(4-chloro-phenyl)- ¹H NMR (CDCl₃) δ 8.9-8.85(d, 1H),ethanone 8.21-8.15(d, 1H), 8.0-7.9(d, 2H), 7.85-7.78 (d, 1H),7.73-7.69(t, 1H), 7.55-7.5 (t, 1H), 7.46-7.4(d, 2H), 7.25-7.19(d, 1H),4.7(s, 2H) 153 1-(3-Chloro-phenyl)-2-quinolin-4- ¹H NMR (CDCl₃) δ8.9-8.85(m, 1H), yl-ethanone 8.21-8.15(m, 1H), 8.0-7.9(m, 2H), 7.85-7.78(m, 1H), 7.73-7.69(m, 1H), 7.55-7.5 (m, 1H), 7.46-7.4(m, 2H),7.25-7.19(m, 1H), 4.7(s, 2H) 154 1-(3-Fluoro-5-trifluoromethyl- ¹H NMR(CDCl₃) δ 8.90-8.88(m, 1H), phenyl)-2-quinolin-4-yl-ethanone8.22-8.12(m, 2H), 7.98-7.75(m, 3H), 7.60-7.52(m, 2H), 7.30-7.25(m, 1H),4.78(s, 2 H) 155 1-Phenyl-2-quinolin-4-yl-ethanone ¹H NMR (CDCl₃) δ8.80-8.75(m, 1 H), 8.20-8.12(m, 3H), 7.80-7.52(m, 3H), 7.35-7.05(m, 4H),4.78(s, 2H) 156 2-(2-Chloro-quinolin-4-yl)-1- ¹H NMR (CDCl₃) δ8.90-8.88(m, 1H), pyridin-2-yl-ethanone 8.10-7.80(m, 3H), 7.85-7.75(m,1H), 7.60-7.52(m, 2H), 7.40(s, 1H), 5.00(s, 2H) 1572-(6,8-Dimethoxy-quinolin-4-yl)-1- ¹H NMR (CDCl₃) δ 8.70-8.65(m, 1H),(6-methyl-pyridin-2-yl)-ethanone 7.87-7.8(m, 1H), 7.75-7.67(m, 1H),7.40-7.3(m, 2H), 6.9-6.85(m, 1H), 6.70-6.65 (m, 1H), 4.9(s, 2H), 4.05(s,3H), 3.85(s, 3H), 2.70(s, 3H) 158 1-(6-Bromo-pyridin-2-yl)-2- ¹H NMR(CDCl₃) δ 8.90-8.85(m, 1H), quinolin-4-yl-ethanone 8.20-8.00(m, 3 H),7.80-7.40(m, 5 H), 4.98(s, 2 H) 159 2-(6,8-Dimethoxy-quinolin-4-yl)-1-¹H NMR (CDCl₃) δ 8.80-8.68(m, 2H), pyridin-2-yl-ethanone 8.1-8.01(m,1H), 7.9-7.8(m, 1H), 7.55-7.48 (m, 1H), 7.42-7.38(m, 1H), 6.9-6.85 (m,1H), 6.70-6.65(m, 1H), 4.9(s, 2H), 4.05(s, 3H), 3.85(s, 3H) 1601-(6-Methyl-pyridin-2-yl)-2- ¹H NMR (CDCl₃) δ 8.85-8.8(m, 1H),quinolin-4-yl-ethanone 8.1-8.0(m, 2H), 7.85-7.87(m, 1H), 7.73-7.6 (m,2H), 7.50-7.43(m, 1H), 7.4-7.3 (m, 2H), 5.00(s, 2H), 2.70(s, 3H) 1612-[1,10]Phenanthrolin-4-yl-1- ¹H NMR (CDCl₃) δ 9.20-9.10(m, 2H),pyridin-2-yl-ethanone 8.80-8.75(m, 1H), 8.25-8.20(m, 1H), 8.05-7.95(m,2H), 7.90-7.75(m, 2H), 7.65-7.50(m, 3H), 5.20(s, 2H) 1622-Quinolin-4-yl-1-thiophen-2-yl- TOF MS ES⁺ exact mass calculated forethanone C₁₅H₁₂NOS (p + 1): m/z = 254.0640 Found: 254.0657 1631-Furan-2-yl-2-quinolin-4-yl- TOF MS ES⁺ exact mass calculated forethanone C₁₅H₁₂NO₂ (p + 1): m/z = 238.0868 Found: 238.0888 1641-(6-Propylpyridin-2-yl)-2-quinolin- TOF MS ES⁺ exact mass calculatedfor 4-yl-ethanone C₁₉H₁₉N₂O (p + 1): m/z = 291.1497 Found: 291.1504 1651-(6-Isopropylpyridin-2-yl)-2- TOF MS ES⁺ exact mass calculated forquinolin-4-yl-ethanone C₁₉H₁₉N₂O (p + 1): m/z = 291.1497 Found: 291.1496166 1-(6-Ethylpyridin-2-yl)-2-quinolin- TOF MS ES⁺ exact mass calculatedfor 4-yl-ethanone C₁₈H₁₇N₂O (p + 1): m/z = 277.1341 Found: 277.1339;Anal. Calcd for C₁₈H₁₆N₂O: C, 78.24; H, 5.84; N, 10.14. Found: C, 77.67;H, 5.92; N, 10.16 167 1-(3-Fluoro-phenyl)-2-quinolin-4-yl- ¹H NMR(CDCl₃): δ 8.87(m, 1H), 8.14 ethanone (m, 1H), 7.83(m, 2H), 7.70(m, 2H),7.55 (m, 2H), 7.42(m, 2H), 4.72(s, 2H) 1681-(4-Fluoro-phenyl)-2-quinolin-4-yl- MS CI⁺ 266 (M + 1) ethanone 1692-(Quinolin-4-yl)-1-(3-trifluoro MS APCI⁺ m/e 332 (M + 1)methoxy-phenyl)-ethanone 170 1-Quinolin-2-yl-2-quinolin-4-yl- MS APCI⁺m/e 299 (M + 1) ethanone 171 1-(4-Ethyl-pyridin-2-yl)-2-quinolin- MSAPCI⁺ m/e 277 (M + 1) 4-yl-ethanone 172 1-[1,8] Naphthyridin-2-yl-2- MSAPCI⁺ m/e 300 (M + 1) quinolin-4-yl-ethanone 1731-(6-Chloro-pyridin-2-yl)-2- ¹H NMR (CDCl₃): δ 8.81(m, 1H), 8.08quinolin-4-yl-ethanone (m, 1H), 7.96(m, 2H), 7.76(m, 1H), 7.63 (m, 1H),7.41(m, 2H), 7.34(m, 1H), 4.94 (s, 2H) 174 1-(4-Chloro-pyridin-2-yl)-2-MS APCI⁺ m/e 283 (M + 1) quinolin-4-yl-ethanone 1751-(2-Fluoro-3-trifluoromethyl- ¹H NMR (CDCl₃): δ 8.20(d, J=4Hz,phenyl)-2-quinolin-4-yl-ethanone 1H), 8.15(d, J=7Hz, 1H), 7.95-8.10(m,1H), 7.60-7.80(m, 3H), 7.50(m, 1H), 7.15-7.35(m, 2H), 4.80(s, 2H) 1761-(4-Fluoro-3-trifluoromethyl- ¹H NMR (CDCl₃): δ 8.85(d, J=4Hz,phenyl)-2-quinolin-4-yl-ethanone 1H), 8.35(d, J=6Hz, 1H), 8.25(m, 1H),8.15(d, J=6Hz, 1H), 7.80(d, J=8Hz, 1H), 7.70(t, J=8Hz, 1H), 7.55(t,J=8Hz, 1H), 7.35(t, J=8Hz, 1H), 7.25(s, 1H), 4.70(s, 2H) 177 Dimethyl6-[2-(4- MS ES⁻ m/e 305 (M − 1) quinolyl)acetyl]pyridyl-2- carboxylate178 2-Quinolin-4-yl-1-(3- MS ES⁺ m/e 315.9 (M + 1)trifluoromethylphenyl)-ethanone 179 1-(5-Chloropyridin-2-yl)-2- mp123-125° C. (quinolin-4-yl)ethanone 180 1-(5-Fluoropyridin-2-yl)-2- MSES⁺ m/e 267 (M + 1) (quinolin-4-yl)ethanone 181 1-(Pyridin-2-yl)-2-(7-mp 87-91° C. chloroquinolin-4-yl)ethanone MS ES⁺ m/e 283 (M + 1), 285(M + 3) 182 1-(6-Methylpyridin-2-yl)-2-(7- mp 88-90° C.chloroquinolin-4-yl)ethanone EA Calcd. for C₁₇H₁₃ClN₂O: C, 68.81; H,4.41; O, 9.44; Found: C, 48.48; H, 4.38; N, 9.63 1831-(6-Methylpyridin-2-yl)-2-(7- MS ES⁺ m/e 308 (M + 2)ethoxyquinolin-4-yl)ethanone 184 2-(4-Fluoronaphthalen-1-yl)-1-(6- MSES⁺ m/e 280 (M + 1) methyl-pyridin-2-yl)-ethanone 1852-Quinolin-4-yl-1-(4-trifluoro ¹H NMR (CDCl₃) δ 8.80(m, 1H), 8.20-8.12methyl-phenyl)-ethanone (m, 3H), 7.90-7.52(m, 5H), 7.25-7.30 (m, 1H),4.78(s, 2H) 186 1-(2-Fluoro-phenyl)-2-quinolin-4-yl- MS CI⁺ 266 (M + 1)ethanone 187 Methyl 6-(2-quinolin-4-yl-acetyl)- MS ES⁻ m/e 305 (M − 1)pyridine-2-carboxylic acid methyl ester 188 2-(6-Bromo-quinolin-4-yl)-1-MS ES⁺ m/e 326.9 & 328.9 (M + 1). pyridin-2-yl-ethanone 1891-Pyridin-2-yl-2-pyridin-4-yl- MS ES⁺ m/e = 199.2 (M + 1) ethanone 1902-(6-Methylpyridin-2-yl)-1- MS ES⁻ m/e 308 (M + 1)quinolin-4-yl-ethanone 191 2-(7-Methoxy-quinolin-4-yl)-1- MS ES⁺ m/e 279(M + 1) pyridin-2-yl-ethanone 192 2-(7-Benzyloxy-6-methoxy- MS ES⁺ m/e385 (M + 1) quinolin-4-yl)-1-pyridin-2-yl- ethanone 1931-Pyrazin-2-yl-2-quinolin-4-yl- MS APCI⁺ m/e 250 (M + 1) ethanone 1942-(6-Bromo-quinolin-4-yl)-1-(6- ¹H NMR (CDCl₃) δ 8.89-8.81(m, 1H),methyl-pyridin-2-yl)-ethanone 8.40(s, 1H), 8.03-7.99(m, 1H), 7.90-7.85(m, 1H), 7.79-7.67(m, 2H), 7.49-7.38(m, 2H), 4.97(s, 2H), 2.71(s, 3H)195 1-(6-Methyl-pyridin-2-yl)-2-(6- ¹H NMR (CDCl₃) δ 8.97-8.94(m, 1H),trifluoromethyl-quinolin-4-yl)- 8.55-8.51(m, 1H), 8.25-8.20(m, 1H),ethanone 7.98-7.93(m, 1H), 7.89-7.83(m, 1H), 7.77-7.69(m, 1H),7.54-7.50(m, 1H), 7.41-7.32(m, 1H), 5.00(s, 2H), 2.69(s, 3H) 1962-(8-Fluoro-quinolin-4-yl)-1-(6- ¹H NMR (CDCl₃) δ 8.90-8.85(m, 1H),methyl-pyridin-2-yl)-ethanone 7.90-7.70(m, 2H), 7.50-7.30(m, 3H),5.05(s, 2H), 2.70(s, 3H) 197 2-(7-Bromo-quinolin-4-yl)-1-(6- ¹H NMR(CDCl₃) δ 8.85(m, 1H), 8.30(s, methyl-pyridin-2-yl)-ethanone 1H),8.00-7.60(m, 4H), 7.45-7.35(m, 2H), 5.05(s, 2H), 2.65(s, 3H). 1982-(6-Trifluoromethoxy-quinolin-4- ¹H NMR (CDCl₃) δ 8.92(m, 1H), 8.42(s,yl)-1-(6-methyl-pyridin-2-yl)- 1H), 8.20(m, 1H), 7.88(m, 1H), 7.80-7.70ethanone (m, 2H), 7.53(m, 1H), 7.40(m, 1H), 5.02(s, 2H), 2.64(s, 3H).199 2-(7-Trifluoromethyl-quinolin-4-yl)- ¹H NMR (CDCl₃) δ 8.88(m, 1H),8.15-8.10 1-(6-methyl-pyridin-2-yl)-ethanone (m, 1H), 8.00(s, 1H),7.98-7.80(m, 2H), 7.75-7.65(m, 1H), 7.50(m, 1H), 7.35-7.33(m, 1H),5.00(s, 2H), 2.70(s, 3H) 200 2-(7-Methoxy-quinolin-4-yl)-1-(6- ¹H NMR(CDCl₃) δ 8.88(m, 1H), 8.15-8.10 methyl-pyridin-2-yl)-ethanone (m, 1H),8.00(s, 1H), 7.98-7.80(m, 2H), 7.75-7.65(m, 1H), 7.50(m, 1H),7.35-7.33(m, 1H), 5.00(s, 2H), 2.70(s, 3H) 2012-(7-Bromo-quinolin-4-yl)-1- ¹H NMR (CDCl₃) δ 8.85(m, 1H), 8.30(s,pyridin-2-yl-ethanone 1H), 8.00-7.60(m, 4H), 7.45-7.35(m, 3H), 5.05(s,2H) 202 2-(2-Chloro-pyridin-4-yl)-1-pyridin- ¹H NMR (CDCl₃) δ 8.85(m,1H), 8.30(s, 2-yl-ethanone 1H), 8.00-7.60(m, 4H), 7.45-7.35(m, 3H),5.05(s, 2H) 203 1-(6-Chloro-pyridin-2-yl)-2- ¹H NMR (CDCl₃): δ 8.88(d,J=4.4Hz, quinolin-4-yl-ethanone 1H), 8.13(d, J=8.0Hz, 1H), 7.97-8.02 (m,2H), 7.80-7.87(m, 1H), 7.72(t, J=8.0Hz, 1H), 7.53-7.60(m, 2H), 7.43(d,J=4.4Hz, 1H), 4.99(s, 2H) 204 1-(6-Methyl-pyridin-2-yl)-2- ¹H NMR(CDCl₃): δ 8.54(d, J=4.4Hz, quinolin-4-yl-ethanone 1H), 8.11(dd, J=8.4,0.9Hz, 1H), 8.07 (dd, J=8.4, 0.9Hz, 1H), 7.85(d, J=7.7Hz, 1H),7.66-7.86(m, 2H), 7.54(td, J=7.0, 1.3Hz, 1H), 7.35-7.45(m, 2H), 5.02 (s,2H), 2.67(s, 3H). 204a 2-Quinolin-4-yl-1-thiazol-2-yl- ES MS 269.3(M + 1) ethanone 204b 1-(1-Methyl-1H-imidazol-2-yl)-2- MS (ES) m/e 252.3(M⁺) quinolin-4-yl-ethanone 204c 2-(4-Fluoro-phenyl)-1-(5-methyl- MS(ES) m/e 236.3 (M⁺) 4H-pyrrol-2-yl)-ethanone 204d1-pyridin-2-yl-2-quinolin-4-yl- ES MS 249 (M + 1) ethanone 204e2-quinolin-4-yl-1-thiazol-2-yl- MS (ES) m/e 255 (M⁺) ethanone 204f1-(1-methyl-1H-imidazol-2-yl)-2- MS (ES) m/e 252 (M⁺)quinolin-4-yl-ethanone

Preparation 2052-(4-Fluoro-phenyl)-3-oxo-3-(6-trifluoromethyl-pyridin-2-yl)-propionitrile

A solution of 4-fluorophenylacetonitrile (0.12 mL, 1.0 mmol) in drytetrahydrofuran (2 mL) is treated dropwise with potassiumbis(trimethylsilyl)amide (0.5 M toluene, 3.0 mL, 1.5 mmol) at 0° C.under an atmosphere of nitrogen. The mixture is stirred 10 min then6-trifluoromethyl-pyridine-2-carbothioic acid S-(4-chloro-phenyl) esteris added all at once. The mixture is allowed to warn to room temperaturethen warmed to reflux for 10 min, at which time the reaction is completeby TLC (methylene chloride). The mixture is allowed to cool then pouredinto 10% citric acid and extracted into methylene chloride. Themethylene chloride solution is dried over magnesium sulfate andconcentrated in vacuo. The residue is purified on a silica gel cartridgeprepared with hexane then eluted with methylene chloride to yield 204 mg(66%)2-(4-fluoro-phenyl)-3-oxo-3-(6-trifluoromethyl-pyridin-2-yl)-propionitrile.MS ES⁻ m/z 307 (M−1).

Preparation 2062-(3-Chloro-4-fluoro-phenyl)-1-(6-methyl-pyridin-2-yl)-ethanone

A dispersion of sodium hydride, (60% in mineral oil, 0.7 g, 17.7 mmol)is added to ethanol (25 mL). When gas evolution ceases,3-chloro-4-fluorophenylacetonitrile (Fluorochemicals, 2.0 g, 11.8 mmol)and 6-methyl-pyridine-2-carboxylic acid methyl ester (1.8 g, 11.8 mmol),are added. The mixture is refluxed for 2.5 h and adjusted to pH 7 with 1N hydrochloric acid. The mixture is concentrated in vacuo. Concentratedhydrochloric acid (50 mL) is added to the mixture after which it isrefluxed for 1.5 h. The mixture is poured over ice and adjusted to pH 8with 5 N sodium hydroxide. The mixture is extracted with methylenechloride and the organic portions dried over anhydrous sodium sulfate.The mixture is filtered and concentrated in vacuo to yield the titlecompound, 2.1 g (68%), as a yellowish solid.

¹H NMR (CDCl₃) δ 7.86-7.83 (m, 1H), 7.73-7.71 (m, 1H), 7.42-7.33 (m,2H), 7.26-7.04 (m, 2H), 4.49 (s, 2H), 2.65 (s, 3H).

By the previous method the following compounds are prepared (unlessotherwise specified)

Product PREP # (Chemical Name) Physical Data 207 2-(2-Chloro-4-fluoro-¹H NMR(CDCl₃) δ 7.87-7.85(m, phenyl)-1-(6-methyl-pyridin-2-yl)- 1H),7.74-7.69(m, 1H), 7.36-7.34(m, ethanone 1H), 7.27-7.14(m, 2H),6.99-6.93(m, 1H), 4.68(s, 2H), 2.65(s, 3H) 2081-(6-Methyl-pyridin-2-yl)- ¹H NMR(CDCl₃) δ 7.87-7.85(m,2-(2,4,5-trifluoro-phenyl)- 1H), 7.75-7.70(m, 1H), 7.37-7.34(m, ethanone1H), 7.15-7.07(m, 1H), 6.98-6.89(m, 1H), 4.55(s, 2H), 2.64(s, 3H) 2092-(4-Fluoro-3- ¹H NMR(CDCl₃) δ 7.86-7.84(m,trifluoromethyl-phenyl)-1-(6- 1H), 7.74-7.62(m, 2H), 7.53-7.49(m,methyl-pyridin-2-yl)-ethanone 1H), 7.36-7.33(m, 1H), 7.16-7.10(m, 1H),4.55(s, 2H), 2.65(s, 3H) 210 2-(4-Fluoro-phenyl)-1-(6- ¹H NMR(CDCl₃): δ7.84(d, J=7.7Hz, methyl-pyridin-2-yl)-ethanone 1H), 7.69(t, J=7.7Hz,1H), 7.25-7.35(m, 4H), 6.95-7.05(m, 1H), 4.50(s, 2H), 2.64(s, 3H).

Preparation 211 1-(6-Methylpyridin-2-yl)-2-p-tolyl-ethanone

To a slurry of magnesium turnings (406 mg, 16.7 mmol) in toluene (10 mL)is added 4-methylbenzylchloride (10 mg, 0.06 mmol) dropwise intetrahydrofuran (0.2 mL). Two drops of 1,2-dibromoethane are added, themixture heated to 50° C., and allowed to cool to room temperature. Thisprocess is repeated until reaction initiates. 4-Methylbenzylchloride(1.5 g, 10 mmol) in tetrahydrofuran (7 mL) is added slowly while keepingthe internal temperature below 32° C. After the addition is complete thereaction is stirred at room temperature for 1 h. The reaction mixture isadded dropwise over 5 minutes to a solution of6-methyl-pyridine-2-carboxylic acid methoxy-methyl-amide (Prep 250, 1 g,5.6 mmol) in toluene (5 mL). The reaction is stirred for an additional45 minutes. The reaction is quenched with 1 N hydrochloric acid andstirred for 30 minutes. The aqueous layer is neutralized with saturatedsodium bicarbonate and extracted twice with ethyl acetate. The combinedorganic extracts are washed with brine, dried (sodium sulfate), filteredand concentrated in vacuo. The crude residue is chromatographed on SiO₂(50% ethyl acetate/hexane to 75% ethyl acetate/hexane) to yield thetitle compound, 633 mg (25%), as a brown oil.

MS ES⁺ m/e 226 (M+1)

By the previous method of the following compounds are essentiallyprepared: (unless otherwise specified)

PREP # Product Name Physical Data 212 1-(6-Methyl-pyridin-2-yl)-2- MSES⁺ m/e 262 (M + 1) naphthalen-1-yl-ethanone

Preparation 2132-(4-Fluoro-phenyl)-1-(6-trifluoromethyl-pyridin-2-yl)-ethanone

A slurry of 2-(4-fluoro-phenyl)-3-oxo-3-(6-trifluoromethyl-pyridin-2-yl)-propionitrile (1.4 g, 4.4 mmol) in 48% HBr iswarmed to reflux for 8 h, allowed to stand at ambient temperature 16 h,then warmed at reflux for 8 h. The mixture is extracted with ether,treated with a small amount of sodium bicarbonate, extracted with ether,made basic with solid sodium hydroxide, and extracted again with ether.Ethereal extracts are combined, dried over magnesium sulfate, andconcentrated in vacuo to a dark oil. The residual oil is purified on asilica gel cartridge prepared with hexane then eluted with methylenechloride to yield 816 mg (65%) of the title compound as a dark oil.

MS ES⁻ m/z 282 (M−1).

By the previous method the following compounds are prepared (unlessotherwise specified):

Product PREP # (Chemical Name) Physical Data 2141-Pyridin-2-yl-2-quinolin-6-yl-ethanone MS ES⁺ m/e 249 (M + 1) 2151-(6-Methyl-pyridin-2-yl)-2-quinolin-6-yl- MS ES⁺ m/e 263 (M + 1)ethanone 216 2-Naphthalen-2-yl-1-pyridin-2-yl-ethanone MS ES⁺ m/e 248(M + 1) 217 1-(6-Methyl-pyridin-2-yl)-2-naphthalen-2-yl- MS ES⁺ m/e 262(M + 1) ethanone 218 2-(4-Methanesulfonyl-phenyl)-1-(6-methyl- MS ES⁺m/e 290 (M + 1) pyridin-2-yl)-ethanone 2191-(6-Methyl-pyridin-2-yl)-2-pyridin-3-yl- MS ES⁺ m/e 213 (M + 1)ethanone 220 1-(3-Fluorophenyl)-2-(4-fluorophenyl)- MS ES⁺ m/e 233(M + 1) ethanone 221 2-(4-Fluoro-naphthalen-1-yl)-1-(6-methyl- MS ES⁺m/e 280 (M + 1) pyridin-2-yl)-ethanone 2222-(3,4-Difluoro-phenyl)-1-(6-methyl-pyridin- MS ES⁺ m/e 248 (M + 1)2-yl)-ethanone 223 2-(4-Methoxyphenyl)-1-(6-methylpyridin-2- TOF MS ES⁺exact mass yl)-ethanone calculated for C₉H₁₀N₂ (p + 1): m/z = 146.0844.Found: 146.0832. 224 2-(4-Fluorophenyl)-1-pyridin-2-yl-ethanone MS FAB⁺m/z = 216.1 (M + 1). 225 2-(4-Methoxyphenyl)-1-pyridin-2-yl-ethanone MSES⁺ m/e 228.1 (M + 1) 226 2-(4-Fluorophenyl)-1-(6-methylpyridin-2- MSES⁺ m/e 230.1 (M + 1) yl)ethanone 2272-(4-Methoxyphenyl)-3-(6-methylpyridin-2- TOF MS ES⁺ exact massyl)-3-oxo-propionitrile calculated for C₁₆H₁₅N₂O₂ (p + 1): m/z =267.1134. Found: 267.1125 228 1-Pyridin-2-yl-2-(4-trifluoro MS ES⁺ m/e266.1 (M + 1) methylphenyl)ethanone

Preparation 229[2-Quinolin-4-yl-1-(3-trifluoromethyl-phenyl)-ethylidene]-hydrazine

A solution of 2-quinolin-4-yl-1-(3-trifluoromethyl-phenyl)-ethanone (1.0g, 3.2 mmol) in ethanol (13 mL) is cooled to 0° C. and treated withhydrazine (0.6 g, 19 mmol) and concentrated hydrochloric acid (0.13 mL,1.6 mmol). The mixture is refluxed for 2 h and concentrated in vacuo.The residue is taken up in dichloromethane and washed with saturatedsodium bicarbonate (30 mL), water (2×30 mL), and brine (30 mL). Thesolution is dried over anhydrous sodium sulfate and filtered. Thefiltrate is concentrated to yield the title compound, 1.0 g (97%), as apale yellow foam.

¹H NMR (CDCl₃) δ 8.80 (m, 1H), 8.28-8.05 (m, 3H), 7.90-7.40 (m, 4H),7.20-7.05 (m, 2H), 5.50 (s, 2H), 4.45 (m, 2H).

By the previous method the following compounds are prepared (unlessotherwise specified).

Product PREP # (Chemical Name) Physical Data 230(1-Pyridin-2-yl-2-quinolin-4-yl- ¹H NMR(CDCl₃) δ 8.70-8.61(m, 1H),8.50-8.40(m, ethylidene)-hydrazine 1H), 8.25-8.03(m, 3H), 7.80-7.55(m,3H), 7.31-7.10(m, 2H), 5.50(s, 2H), 4.80(s, 2H) 231[2-Quinolin-4-yl-1-(4- ¹H NMR(CDCl₃) δ 8.82-8.78(m, 1H), 8.20-8.05(m,trifluoromethyl-phenyl)- 2H), 7.85-7.60(m, 5H), 7.30-7.10(m,ethylidene]-hydrazine 2H), 5.55(s, 2H), 4.44(s, 2H) 232[1-(4-Chloro-phenyl)-2-quinolin- ¹H NMR(CDCl₃) δ 8.79-8.7(m, 1H),8.22-8.15(d, 4-yl-ethylidene]-hydrazine 1H), 8.13-8.03(d, 2H),7.84-7.75(m, 1H), 7.72-7.63(m, 1H), 7.6-7.52(d, 2H), 7.38-7.25(m, 1H),7.1-7.0(m, 1H), 5.45(s, 2H), 4.4(s, 2H) 233[1-(3-Chloro-phenyl)-2-quinolin- ¹H NMR(CDCl₃) δ 8.79-8.7(m, 1H),8.22-8.00(m, 4-yl-ethylidene]-hydrazine 3H), 7.8-7.69(m, 2H),7.84-7.5-7.42(m, 1H), 7.3-7.2(m, 2H), 7.10-6.98(m, 1H), 5.50(s, 2H),4.40(s, 2H) 234 [1-(3-Fluoro-5-trifluoromethyl- ¹H NMR(CDCl₃) δ8.82-8.78(m, 1H), 8.20-8.05(m, phenyl)-2-quinolin-4-yl- 2H),7.85-7.70(m, 3H), 7.55-7.48(m, ethylidene]-hydrazine 1H), 7.30-7.22(m,1H), 7.05-7.00(m, 1H), 5.60(s, 2H), 4.40(s, 2H) 235(1-Phenyl-2-quinolin-4-yl- ¹H NMR(CDCl₃) δ 8.82-8.78(m, 1H),8.30-8.05(m, ethylidene)-hydrazine 2H), 7.80-7.60(m, 4H), 7.40-7.15(m,4H), 5.40(s, 2H), 4.50(s, 2H) 236 [2-(2-Chloro-quinolin-4-yl)-1- ¹HNMR(CDCl₃) δ 8.50-8.45(m, 1H), 8.20-8.00(m, pyridin-2-yl-ethylidene]-3H), 7.80-7.60(m, 3H), 7.25-7.18(m, hydrazine 1H), 7.00(s, 1H), 5.60(s,2H), 4.70(s, 2H) 237 [2-(6,8-Dimethoxy-quinolin-4- ¹H NMR(CDCl₃) δ8.70-8.65(m, 1H), 7.87-7.80(m, yl)-1-(6-methyl-pyridin-2-yl)- 1H),7.75-7.67(m, 1H), 7.20-7.13(m, ethylidene]-hydrazine 1H), 7.10-7.03(m,1H), 6.90-6.85(m, 1H), 6.7-6.65(m, 1H), 5.50(s, 2H), 4.70(s, 2H),4.05(s, 3H), 3.85(s, 3H), 2.70(s, 3H) 238 [1-(6-Bromo-pyridin-2-yl)-2-¹H NMR(CDCl₃) δ 8.82-8.78(m, 1H), 8.25-8.00(m,quinolin-4-yl-ethylidene]- 3H), 7.85-7.60(m, 3H), 7.40-7.35(m, hydrazine1H), 7.10-7.05(m, 1H), 5.55(s, 2H), 4.70(s, 2H) 239[2-(6,8-Dimethoxy-quinolin-4- ¹H NMR(CDCl₃) δ 8.69-8.50(m, 2H),8.10-8.01(m, yl)-1-pyridin-2-yl-ethylidene]- 1H), 7.75-7.67(m, 1H),7.25-7.10(m, hydrazine 2H), 6.90-6.85(m, 1H), 6.70-6.65(m, 1H), 5.57(s,2H), 4.67(s, 2H), 4.05(s, 3H), 3.85(s, 3H) 240[1-(6-Methyl-pyridin-2-yl)-2- ¹H NMR(CDCl₃) δ 8.75-8.68(m, 1H),8.27-8.20(d, quinolin-4-yl-ethylidene]- 1H), 8.19-8.1(d, 1H),7.90-7.82(m, hydrazine 1H), 7.80-7.69(m, 2H), 7.65-7.50(m, 1H),7.10-7.00(m, 2H), 5.50(s, 2H), 4.80(s, 2H), 2.45(s, 3H) 241(2-[1,10]Phenanthrolin-4-yl-1- ¹H NMR(CDCl₃) δ 9.20-9.05(m, 2H),8.85-8.80(m, pyridin-2-yl-ethylidene)- 1H), 8.45-8.40(m, 1H),8.30-8.05(m, hydrazine 3H), 7.90-7.75(m, 2H), 7.65-7.50(m, 2H), 5.60(brs, 2H), 4.90(s, 2H) 242 [1-(3-Fluoro-phenyl)-2-quinolin- ¹H NMR(CDCl₃):δ 8.75(m, 1H), 8.05(m, 4-yl-ethylidene]-hydrazine 2H), 7.68(m, 1H),7.51(m, 1H), 7.32(m, 3H), 6.93(m, 1H), 6.86(m, 1H), 5.45(s, 2H), 4.32(s,2H) 243 [1-(2-Fluoro-phenyl)-2-quinolin- ¹H NMR(CDCl₃, 1:1 mixture ofrotamers): δ 4-yl-ethylidene]-hydrazine 8.73(m, 1H), 8.07(m, 2H),7.51(m, 2H), 6.81(m, 2H), 5.38(m, 2H), 4.30(m, 2H) 244[1-(4-Fluoro-phenyl)-2-quinolin- MS Calcd. 279; MS (CI) (M + 1) 2804-yl-ethylidene]-hydrazine 245 [2-Quinolin-4-yl-1-(3- ¹H NMR(CDCl₃): δ8.78(m, 1H), 8.21(m, trifluoromethoxy-phenyl)- 2H), 7.62(m, 4H), 7.22(m,3H), 5.53(s, ethylidene]-hydrazine 2H), 4.42(s, 2H) 246(2-Quinolin-4-yl-1-quinolin-2- MS Calcd. 312; MS (APCI) (M + 1) 313yl-ethylidene)-hydrazine 247 [1-(4-Ethyl-pyridin-2-yl)-2- MS Calcd. 290;MS (API) (M + 1) 291 quinolin-4-yl-ethylidene]- hydrazine 248(1-[1,8]Naphthyridin-2-yl-2- MS Calcd. 313; MS (APCI) (M + 1) 314quinolin-4-yl-ethylidene)- hydrazine 249 [1-(6-Chloropyridin-2-yl)-2- MSCalcd. 296; MS (APCI) (M + 1) 297 quinolin-4-yl-ethylidene]- hydrazine250 [1-(4-Chloropyridin-2-yl)-2- MS Calcd. 296; MS (APCI) (M + 1) 297quinolin-4-yl-ethylidene]- hydrazine 251 [1-(2-Fluoro-3-trifluoromethyl-¹H NMR(CDCl₃): δ 8.80(m, 1H), 7.95- phenyl)-2-quinolin-4-yl- 8.20(m,2H), 7.40-7.80(m, 4H), 7.00-7.30(m, ethylidene]-hydrazine 2H), 5.80(s,2H), 4.45(s, 2H)

Preparation 2524-Benzyl-1-(1-pyridin-2-yl-2-quinolin-4-yl-ethylideneamino)-pyrrolidin-2-one

A mixture of 3-benzyl-4-bromo-butyricacid(1-pyridin-2-yl-2-quinolin-4-yl-ethylidene)-hydrazide (PREP. 70, 0.8g, 1.6 mmol) in tetrahydrofuran (26 mL) at 0° C. is treated with NaH(60% in mineral oil, 0.086 g, 2.2 mmol). The mixture is warmed to roomtemperature and stirred for 2 h. Saturated ammonium chloride (2 mL) isadded and volatiles removed in vacuo. The residue is chromatographed onSiO₂ (90% ethyl acetate/hexanes followed bydichloromethane:methanol:ammonium hydroxide/94:5:1) to yield the titlecompound, 0.4 g (45%), as a yellowish foam.

¹H NMR (CDCl₃) δ 8.86-8.82 (m, 1H), 8.70-8.60 (m, 1H), 8.30-8.05 (m,3H), 7.80-7.30 (m, 4H), 7.30-7.20 (m, 5H), 6.85-6.80 (m, 1H), 5.20-4.85(m, 2H), 3.05-2.95 (m, 2H), 2.30-2.15 (m, 3H), 2.00-1.90 (m, 2H).

By the previous method the following compounds are essentially prepared:

Product PREP # (Chemical Name) Physical Data 253 1-(1-Pyridin-2-yl-2- ¹HNMR(CDCl₃) δ 8.80-8.70(m, 2H), 8.20-8.00(m, quinolin-4-yl- 3H),7.80-7.66(m, 3H), 7.60-7.40(m, 1H), ethylideneamino)- 7.30-7.10(m, 5H),6.95-6.90(m, 1H), 5.20-5.10(m, pyrrolidin-2-one 1H), 4.80-4.70(m, 1H),3.00-3.85(m, 2H), 2.70-2.60(m, 1H), 2.40-2.10(m, 6H) 2544-Phenyl-1-(1-pyridin-2-yl- ¹H NMR(CDCl₃) δ 8.75-8.61(m, 2H),2.27-8.00(m, 2-quinolin-4-yl-ethylidiene 2H), 7.80-7.60(m, 2H),7.53-7.45(m, 2H), amino)-pyrrolidin-2-one 7.20-7.10(m, 6H), 6.88-6.80(m,1H), 5.25-5.20(m, 1H), 4.78-4.70(m, 1H), 3.40-3.33(m, 1H), 3.15-3.05(m,1H), 2.7-2.48(m, 2H), 2.40-2.30(m, 1H) 255 1-[2-Quinolin-4-yl-1-(3- ¹HNMR(CDCl₃) δ 8.98(s, 1H), 8.72-8.80(m, trifluoromethylphenyl)- 1H),8.20-8.25(m, 1H), 8.00-8.10(m, 2H), 7.60-7.88(m, ethylideneamino]- 3H),7.40-7.50(m, 1H), 6.78-6.90(m, pyrrolidin-2-one 1H), 4.51(s, 2H),3.55-3.65(m, 2H), 2.88-2.98(m, 2H), 2.00-2.20(m, 2H) 2561-[2-Quinolin-4-yl-1-(4- ¹H NMR(CDCl₃) δ 8.80-8.00(m, 1H),trifluoromethyl-phenyl)- 8.20-8.10(m, 2H), 8.00-7.60(m, 5H),7.25-7.10(m, 2H), ethylideneamino]- 3.48-3.40(m, 2H), 2.35-2.25(m, 2H),pyrrolidin-2-one 1.80-1.65(m, 2H) 257 1-(1-Phenyl-2-quinolin-4- ¹HNMR(CDCl₃) δ 8.80-8.75(m, 1H), yl-ethylideneamino)- 8.15-8.00(m, 2H),7.80-7.50(m, 3H), 7.40-7.10(m, 5H), pyrrolidin-2-one 4.60(s, 2H),3.35-3.30(m, 2H), 2.30-2.20(m, 2H), 1.70-1.60(m, 2H) 2581-[2-(2-Chloro-quinolin-4- ¹H NMR(CDCl₃) δ 8.70-8.60(m, 1H),yl)-1-pyridin-2-yl- 8.20-7.95(m, 2H), 7.80-7.65(m, 2H), 7.60-7.10(m,4H), ethylideneamino]- 4.90(s, 2H), 3.10-3.05(m, 2H), 2.25-2.15(m,pyrrolidin-2-one 2H), 1.60-1.40(m, 2H) 259 1-[2-(6,8-Dimethoxy- ¹HNMR(CDCl₃) δ 8.70-8.65(m, 1H), quinolin-4-yl)-1-(6-methyl- 7.90-7.83(m,1H), 7.65-7.57(m, 1H), 7.25-7.15(m, 2H), pyridin-2-yl)-ethylidene6.9-6.87(m, 1H), 6.67-6.63(m, 1H), 4.80(s, amino]-pyrrolidin-2-one 2H),4.00(s, 3H), 3.70(s, 3H), 2.95-2.87(m, 2H), 2.60(s, 3H), 2.20-2.08(m,2H), 1.4-1.3(m, 2H) 260 1-[1-(6-Bromo-pyridin-2- ¹H NMR(CDCl₃) δ8.80-8.75(m, 1H), yl)-2-quinolin-4-yl- 8.15-8.10(m, 2H), 7.95-7.90(m,1H), 7.70-7.45(m, 4H), ethylideneamino]- 7.20-7.15(m, 1H), 4.85(s, 2H),3.10-3.00(m, pyrrolidin-2-one 2H), 2.20-2.15(m, 2H), 1.50-1.30(m, 2H)261 1-[2-(6,8-Dimethoxy- ¹H NMR(CDCl₃) δ 8.7-8.4(m, 3H),quinolin-4-yl)-1-pyridin-2- 7.83-7.70(m, 1H), 7.4-7.2(m, 2H),6.9-6.87(m, 1H), yl-ethylidene amino]- 6.67-6.63(m, 1H), 4.80(s, 2H),4.10-3.80(m, 7H), pyrrolidin-2-one 3.7(s, 3H), 2.20-2.08(m, 2H) 2621-[1-(3-Fluoro-phenyl)-2- MS APCI⁺ m/e 348 (M + 1) quinolin-4-yl-ethylideneamino]- pyrrolidin-2-one 263 1-[1-(2-Fluoro-phenyl)-2-quinolin-4-yl- ethylideneamino]- pyrrolidin-2-one 2641-[1-(4-Fluoro-phenyl)-2- MS APCI⁺ m/e 348 (M + 1) quinolin-4-yl-ethylideneamino]- pyrrolidin-2-one 265 1-[2-Quinolin-4-yl-1-(3- ¹HNMR(CDCl₃): δ 8.75(m, 1H), 8.15(m, 2H), trifluoromethoxy-phenyl)-7.55(m, 4H), 7.48(m, 1H), 7.12(m, 2H), 4.55(s, ethylideneamino]- 2H),3.44(m, 2H), 2.24(m, 2H), 1.63(m, 2H) pyrrolidin-2-one 2664-[2-(4-Fluoro-phenyl)- MS APCI⁺ m/e 344 (M + 1) 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3- yl]-quinoline 267 1-(2-Quinolin-4-yl-1- MSAPCI⁺ m/e 381 (M + 1) quinolin-2-yl- ethylideneamino)- pyrrolidin-2-one268 1-[1-(6-Chloro-pyridin-2- MS APCI⁺ m/e 365 (M + 1)yl)-2-quinolin-4-yl- ethylideneamino]- pyrrolidin-2-one 2691-[1-(4-Chloro-pyridin-2- MS APCI⁺ m/e 365 (M + 1) yl)-2-quinolin-4-yl-ethylideneamino]- pyrrolidin-2-one 270 1-[1-(2-Fluoro-3- ¹H NMR(CDCl₃):δ 8.70-8.80(m, 1H), 8.00-8.20(m, trifluoromethyl-phenyl)-2- 2H),7.50-7.70(m, 4H), 7.00-7.30(m, quinolin-4-yl- 2H), 4.50(s, 2H), 3.60(m,2H), 2.10-2.40(m, ethylideneamino]- 2H), 1.75-2.00(m, 2H)pyrrolidin-2-one 271 1-(Benzhydrylidene- ¹H NMR(CDCl₃): δ 1.80(q, J=9Hz,2H), amino)-pyrrolidin-2-one 2.30(t, J=9Hz, 2H), 3.30(t, J=9Hz, 2H),7.30(m, 8H), 7.50(m, 2H) 272 1-(Benzhydrylidene- ¹H NMR(CDCl₃): δ7.65(d, J=8Hz, 2H), 7.20-7.50(m, amino)-4-(4-fluoro- 10H), 6.95(d,J=6Hz, 2H), 3.70(dd, J=7, phenyl)-pyrrolidin-2-one 9Hz, 1H),3.25-3.50(m, 2H), 2.75(dd, J=9, 17Hz, 1H), 2.45(dd, J=7, 17Hz, 1H,) 2731-(Benzhydrylidene- ¹H NMR(CDCl₃): δ 7.60(m, 2H), 7.22-7.45(m,amino)-4-(3-methoxy- 9H), 6.75(dd, J=2.5, 8Hz, 1H), 6.60(m, 2H),phenyl)-pyrrolidin-2-one 3.80(s, 3H), 3.65(m, 1H), 3.30-3.45(m, 2H),2.85(dd, J=9, 17Hz, 1H), 2.45(dd, J=9, 17Hz, 1H) 274 1-(Benzhydrylidene-¹H NMR(CDCl₃): δ 7.50-7.60(m, 5H), 7.30-7.40(m, amino)-5-(tert-butyl-5H), 3.95(dd, J=4, 10.5Hz, 1H), 3.70-3.80(m, dimethyl-silyloxymethyl)-1H), 3.60(dd, J=4, 10.5Hz, 1H), 2.30-2.45(m, pyrrolidin-2-one 1H),2.10-2.25(m, 1H), 1.90-2.05(m, 2H), 0.90(s, 9H), 0.10(s, 6H) 2751-[1-(6-Methyl-pyridin-2- MS APCI⁺ m/e 346 (M + 1) yl)-2-quinolin-4-yl-ethylideneamino]- pyrrolidin-2-one 276 1-[2-(6,7-Dimethoxy- MS ES⁺ m/e405 (M + 1) quinolin-4-yl)-1-(6-methyl- pyridin-2-yl)- ethylideneamino]-pyrrolidin-2-one 278 1-(1-Pyrazin-2-yl-2- ¹H NMR(CDCl₃): δ 9.39(s, 1H),8.77(m, 1H), quinolin-4-yl- 8.65(m, 1H), 8.58(m, 1H), 8.13(m, 1H),7.96(m, ethylideneamino)- 1H), 7.72(m, 1H), 7.51(m, 1H), 7.18(m,pyrrolidin-2-one 1H), 4.84(s, 2H), 3.15(m, 2H), 2.21(m, 2H), 1.47(m, 2H)279 4-Methyl-1-(1-pyridin-2- ¹H NMR(CDCl₃) δ 8.80-8.73(m, 1H),8.70-8.63(m, yl-2-quinolin-4-yl- 1H), 8.20-8.00(m, 3H), 7.81-7.68(m,2H), ethylideneamino)- 7.55-7.47(m, 1H), 7.40-7.35(m, 1H), 7.21-7.18(m,pyrrolidin-2-one 1H), 5.17-5.07(m, 1H), 4.80-4.72(m, 1H), 3.07-2.99(m,1H), 2.90-2.82(m, 1H), 2.39-2.23(m, 1H), 1.87-1.55(m, 2H), 0.79-0.67(m,3H) 280 1-[1-(6-Methyl-pyridin-2- ¹H NMR(CDCl₃) δ 8.89-8.80(m, 1H),8.59(s, yl)-2-(6-trifluoromethyl- 1H), 8.24-8.17(m, 1H), 7.91-7.78(m,2H), 7.65-7.55(m, quinolin-4-yl)- 1H), 7.41-7.39(m, 1H), 7.20-7.13(m,ethylideneamino]- 1H), 4.91(s, 2H), 3.22-3.13(m, 2H), 2.49(s,pyrrolidin-2-one 3H), 2.37-2.29(m, 2H), 1.72-1.57(m, 2H) 281(S)-1-(Benzhydrylidene- ¹H NMR(CDCl₃): δ 7.56-7.60(m, 2H), 7.24-7.46(m,amino)-5-benzyloxy 13H), 4.55-4.72(m, 2H), 3.90(m, 1H),methyl-pyrrolidin-2-one 3.76(dd, J=9.8, 4.3Hz, 1H), 3.60(dd, J=9.8,3.2Hz, 1H), 1.95-2.39(m, 4H). 282 4-[1-(Benzhydrylidene- ¹H NMR(CDCl₃):δ 7.93(d, J=8.0Hz, 2H), amino)-5-oxo-pyrrolidin-3- 7.63(dd, J=8.0,J=0.7Hz, 2H), 7.29-7.54(m, yl]-benzoic acid ethyl ester 10H), 4.36(q,J=7.1Hz, 2H), 3.78(dd, J=9.3, 8.1Hz, 1H), 3.46-3.63(m, 1H), 3.36(dd,J=9.3, 6.0Hz, 1H), 2.81(dd, J=17.0, 9.2Hz, 1H), 2.45(dd, J=17.0, 6.9Hz,1H), 1.39(t, J=7.1Hz, 3H) 283 1-(Benzhydrylidene- ¹H NMR(CDCl₃): δ7.27-7.64(m, 10H), 3.03(s, amino)-4,4-dimethyl- 2H), 2.14(s, 2H),0.97(s, 6H) pyrrolidin-2-one 284 (R)-1-(Benzhydrylidene- ¹H NMR(CDCl₃):δ 7.56-7.60(m, 2H), 7.24-7.46(m, amino)-5-benzyloxy 13H), 4.55-4.72(m,2H), 3.90(m, 1H), methyl-pyrrolidin-2-one 3.76(dd, J=9.8, 4.3Hz, 1H),3.60(dd, J=9.8, 3.2Hz, 1H), 1.95-2.39(m, 4H) 285 1-(Benzhydrylidene- ¹HNMR(CDCl₃): δ 7.61(m, 2H), 7.21-7.47(m, amino)-4-(4-chloro- 10H),6.93(m, 2H), 3.75(dd, J=9.2, 7.9Hz, phenyl)-pyrrolidin-2-one 1H),3.25-3.48(m, 2H), 2.78(dd, J=17.2, 9.0Hz, 1H), 2.40(dd, J=17.2, 6.8Hz,1H)  285a 1-[1-(4-Methyl-thiazol-2- ES MS 351.4 (M + 1)yl)-2-quinolin-4-yl- ethylideneamino]- pyrrolidin-2-one  285b1-[1-(1-Methyl-1H- MS (ES) m/e 334.4 (M⁺) imidazol-2-yl)-2-quinolin-4-yl-ethylideneamino]- pyrrolidin-2-one  285c 1-[2-(4-Fluoro-phenyl)-1-MS (ES) m/e 318.4 (M⁺) (4-methyl-thiazol-2-yl)- ethylideneamino]-pyrrolidin-2-one  285d 1-pyridin-2-yl-2-quinolin- ES MS 249 (M + 1)4-yl-ethanone  285e 1-(2-quinolin-4-yl-1- MS (ES) m/e 337 (M⁺)thiazol-2-yl- ethylideneamino)- pyrrolidin-2-one  285f1-[1-(1-methyl-1H- MS (ES) m/e 334 (M⁺) imidazol-2-yl)-2-quinolin-4-yl-ethylideneamino]- pyrrolidin-2-one  285g 1-[2-(6,7-Dichloro- MS ES⁺m/e 413 (M + 1) quinolin-4-yl)-1-(6-methyl- pyridin-2-yl)-ethylideneamino]- pyrrolidin-2-one

Preparation 2864-(3-Methoxy-phenyl)-1-(1-pyridin-2-yl-2-quinolin-4-yl-ethylideneamino)-pyrrolidin-2-one

A solution of 1-pyridin-2-yl-2-quinolin-4-yl-ethanone, (0.25 g, 1 mmol)and pyridine (0.242 mL, 3 mmol) in acetic acid (2 mL) is added to1-amino-4-(3-methoxy-phenyl)-pyrrolidin-2-one, (0.2 g, 1 mmol) at roomtemperature under nitrogen. The mixture is stirred 18 h and concentratedin vacuo. The residue is chromatographed on SiO₂ (2%methanol/dichloromethane) to yield the title compound, 0.25 g (57%), asa yellow foam.

¹H NMR (CDCl₃): δ 8.75 (d, J=4.5 Hz, 1H), 8.65 (d, J=4.5 Hz, 1H),7.70-8.20 (m, 3H), 7.20-7.60 (m, 3H), 6.70-6.85 (m, 3H), 6.40-6.55 (m,3H), 5.25 (d, J=16.7 Hz, 1H), 4.70 (d, J=16.7 Hz, 1H), 3.70 (s, 3H),3.45-3.60 (m, 1H), 3.10 (dd, J=8, 9.3 Hz, 1H), 2.25-2.80 (m, 3H).

By the previous method the following compounds are prepared (unlessotherwise specified):

Product PREP # (Chemical Name) Physical Data 287 1-[1-(4-Fluoro-3- ¹HNMR(CDCl₃): δ 8.70(d, J=4Hz, 1H), trifluoromethyl-phenyl)-2- 8.10(t,J=8Hz, 2H), 7.80-7.95(m, 2H), quinolin-4-yl- 7.70(t, J=8Hz, 1H), 7.55(t,J=8Hz, 1H), ethylideneamino]-pyrrolidin-2- 7.00-7.20(m, 2H), 4.50(s,2H), 3.45(t, J=7Hz, one 2H), 2.25(t, J=7Hz, 2H), 1.75(q, J=7Hz, 2H) 2881-[1-(4-Fluoro-3- ¹H NMR(CDCl₃): δ 8.80(d, J=4.5Hz, 1H),trifluoromethyl-phenyl)-2- 8.15(d, J=8.5Hz, 1H), 7.65-8.00(m, 4H),quinolin-4-yl- 7.00-7.40(m, 4H), 6.55-6.80(m, 3H), 4.65(s,ethylideneamino]-4-(3- 2H), 3.75(m, 5H), 3.15(m, 1H), 2.75(dd, J=8.5,methoxy-phenyl)-pyrrolidin-2- 17Hz, 1H), 2.50(dd, J=8.5, 17Hz, 1H) one289 4-(4-Fluoro-phenyl)-1-(1- ¹H NMR(CDCl₃): δ 8.80(d, J=4.5Hz, 1H),pyridin-2-yl-2-quinolin-4-yl- 8.70(d, J=4.5Hz, 1H), 8.00-8.25(m, 3H),ethylideneamino)-pyrrolidin-2- 7.60-7.90(m, 2H), 7.45-7.60(m, 2H),7.15-7.25(m, one 2H), 6.75-6.85(m, 3H), 5.20(d, J=16.8Hz, 1H), 4.70(d,J=16.8Hz, 1H), 3.30 (t, J=9Hz, 1H), 3.15(t, J=9Hz, 1H), 2.70(m, 1H),2.55(dd, J=9, 16.8Hz, 1H), 2.25(dd, J=9, 16.8Hz, 1H) 2905-Hydroxymethyl-1-(1-pyridin- ¹H NMR(CDCl₃): δ 8.70(d, J=4.5Hz, 1H),2-yl-2-quinolin-4-yl- 8.00-8.15(m, 2H), 7.80(d, J=8Hz, 1H),ethylideneamino)-pyrrolidin-2- 7.15-7.75(m, 6H), 4.95(d, J=16.5Hz, 1H),one 4.85(d, J=16.5Hz, 1H), 3.25-3.45(m, 2H), 3.10-3.20(m, 1H),2.10-2.40(m, 3H), 1.20-1.60(m, 2H) 291 4-(4-Fluoro-phenyl)-1-[1-(6- ¹HNMR(CDCl₃): δ 8.85(d, J=4.5Hz, 1H), methyl-pyridin-2-yl)-2- 7.95-8.25(m,3H), 7.20-7.60(m, 5H), 6.80-6.90(m, quinolin-4-yl- 4H), 5.25(d,J=16.6Hz, 1H), 4.70 ethylideneamino]-pyrrolidin-2- (d, J=16.6Hz, 1H),3.10- 3.35(m, 2H), 2.60-2.70(m, one 1H), 2.40-2.50(m, 1H), 2.55(s, 3H),2.20-2.40(m, 1H) 292 3-Benzyl-1-[1-(6-methyl- MS ES⁺ m/e 421 (M + 1)pyridin-2-yl)-2-quinolin-4-yl- ethylideneamino]-pyrrolidin-2- one 2933-Ethyl-1-[1-(6-methyl-pyridin- MS ES⁺ m/e 359 (M + 1)2-yl)-2-quinolin-4-yl- ethylideneamino]-pyrrolidin-2- one 2941-(1-Pyridin-2-yl-2-quinolin-4- MS ES⁺ m/e 359.0 (M + 1)yl-ethylideneamino)-piperidine- 2,6-dione 2951-[2-(7-Chloroquinolin-4-yl)-1- mp 87-91° C. (pyridin-2- MS ES⁺ m/e 283(M + 1), 285 (M + 3) yl)ethylideneamino]pyrrolidin- 2-one 2961-[2-(7-Chloroquinolin-4-yl)-1- mp 151-153° C. (6-methylpyridin-2- EACalcd for C₂₁H₁₉N₄O: C, 66.58; H, 5.06; N,yl)ethylideneamino]pyrrolidin- 14.79; Found: C, 66.48; H, 5.15; N, 14.422-one 297 1-[2-(7-Ethoxyquinolin-4-yl)-1- MS ES⁺ m/e 390 (M + 2)(6-methylpyridin-2- yl)ethylideneamino]pyrrolidin- 2-one 2981-[2-(4-Fluorophenyl)-1- MS ES+ m/e 298.1 (M + 1). pyridin-2-yl-ethylideneamino]pyrrolidin-2- one 299 1-[2-(4-Methoxyphenyl)-1- MS ES⁺m/e 310.1 (M + 1). pyridin-2-yl- ethylideneamino]pyrrolidin-2- one 3001-[2-(4-Fluorophenyl)-1-(6- methylpyridin-2-yl)- MS ES⁺ m/e 312.1(M + 1) ethylideneamino]pyrrolidin-2- one 3011-[2-(4-Methoxyphenyl)-1-(6- MS ES⁺ m/e 324.1 (M + 1).methylpyridin-2-yl) ethylideneamino]pyrrolidin-2- one 3021-(2-Quinolin-4-yl-1-thiophen- MS ES⁺ m/e 336.1 (M + 1) 2-yl-ethylideneamino)pyrrolidin-2- one 303 4-(2-Furan-2-yl-5,6-dihydro- TOFMS ES⁺ exact mass calculated for 4H-pyrrolo[1,2-b]pyrazol-3- C₁₉H₁₆N₃O(p + 1): m/z = 302.1293. Found: yl)-quinoline 302.1312 3041-[1-(6-Propylpyridin-2-yl)-2- MS ES⁺ m/e 373.1 (M + 1) quinolin-4-yl-ethylideneamino]pyrrolidin-2- one 305 1-[1-(6-Isopropylpyridin-2-yl)- MSES⁺ m/e 373.1 (M + 1) 2-quinolin-4-yl- ethylideneamino]pyrrolidin-2- one306 1-(1-Pyridin-2-yl-2-quinolin-4- MS ES⁺ m/e 330.9 (M + 1)yl-ethylideneamino)-pyrrolidin- 2-one 307 3-Methyl-1-[(pyridin-2-yl- MSES⁺ m/e 345 (M + 1) quinolin-4-yl-methylene)- amino]-pyrrolidin-2-one308 6-[1-(2-Oxo-pyrrolidin-1- MS ES⁺ m/e 389 (M + 1)ylimino)-2-quinolin-4-yl- ethyl]-pyridine-2-carboxylic acid methyl ester309 6-[1-(2-Oxo-pyrrolidino-1- MS ES⁺ m/e 389 (M + 1)ylimino)-2-quinolin-4-yl-ethyl] pyridine-2-carboxylic acid methyl ester310 1-Pyridin-2-yl-2-quinolin-6-yl- MS ES⁺ m/e 249 (M + 1) ethanone 3111-(6-Methyl-pyridin-2-yl)-2- MS ES⁺ m/e 263 (M + 1)quinolin-6-yl-ethanone 312 2-Naphthalen-2-yl-1-pyridin-2- MS ES⁺ m/e 248(M + 1) yl-ethanone 313 1-(6-Methyl-pyridin-2-yl)-2- MS ES⁺ m/e 262(M + 1) naphthalen-2-yl-ethanone 314 1-[2-(4-Fluoro-phenyl)-1-(6- MS ES⁺m/z 366 (M + 1). trifluoromethyl-pyridin-2-yl)-ethylideneamino]-pyrrolidin-2- one 315 1-[2-(6-Bromo-quinolin-4-yl)- MSES⁺ m/e 408.7 & 410.7 (M + 1) 1-pyridin-2-yl-ethylideneamino]-pyrrolidin-2- one 316 1-(2-Pyridin-4-yl-1-pyridin-2- MSES⁺ m/e yl-ethylideneamino)-pyrrolidin- 281.3 (M + 1) 2-one 3171-[1-(6-Methylpyridin-2-yl)-2- MS ES⁺ m/e 308 (M + 1)p-tolyl-ethylideneamino]- pyrrolidin-2-one 3181-[2-(6-Methylpyridin-2-yl)-1- MS ES⁺ m/e 245 (M + 1) quinolin-4-yl-ethylideneamino]-pyrrolidin-2- one 319 1-[1-(6-Methylpyridin-2-yl)-2- MSES⁺ m/e 344 (M + 1) naphthalen-1-yl- ethylideneamino]-pyrrolidin-2- one320 1-[1-(6-Methylpyridin-2-yl)-2- MS ES+ m/e 295 (M + 1)pyridin-3-yl-ethylideneamino]- pyrrolidin-2-one 3211-[2-(4-Fluorophenyl)-1-(3- MS ES+ m/e 315 (M + 1) fluorophenyl)-ethylideneamino]-pyrrolidin-2- one 323 1-[2-(4-Fluoronaphthalen-1-yl)-MS ES⁺ m/e 362 (M + 1) 1-(6-methylpyridin-2-yl)-ethylideneamino]-pyrrolidin-2- one 324 1-[2-(3,4-Difluorophenyl)-1-(6-MS ES⁺ m/e 329.9 (M + 1) methylpyridin-2-yl)-ethylideneamino]-pyrrolidin-2- one 325 1-[2-(4-Methanesulfonyl- MS ES⁺m/e 372 (M + 1) phenyl)-1-(6-methyl-pyridin-2- yl)-ethylideneamino]-pyrrolidin-2-one 326 1-[2-(7-Methoxy-quinolin-4- MS ES⁺ m/e 361 (M + 1)yl)-1-pyridin-2-yl- ethylideneamino]-pyrrolidin-2- one 3271-[2-(7-Benzyloxy-6-methoxy- MS ES⁺ m/e 467 (M + 1)quinolin-4-yl)-1-pyridin-2-yl- ethylideneamino]-pyrrolidin-2- one 3281-[2-(6-Bromo-quinolin-4-yl)- ¹H NMR(CDCl₃) δ 8.74-8.70(m, 1H),8.39-8.35(m, 1-(6-methyl-pyridin-2-yl)- 1H), 7.96-7.84(m, 2H),7.78-7.72(m, ethylideneamino]-pyrrolidin-2- 1H), 7.64-7.56(m, 1H),7.34-7.28(m, one 1H), 7.21-7.15(m, 1H), 4.80(s, 2H), 3.34-3.27(m, 2H),2.54(s, 3H), 2.38-2.30(m, 2H), 1.73-1.59(m, 2H) 3291-[2-(3-Chloro-4-fluoro- ¹H NMR(CDCl₃) δ 7.89-7.87(m, 1H), 7.62-7.57(m,phenyl)-1-(6-methyl-pyridin-2- 1H), 7.30-7.27(m, 1H), 7.19-7.17(m,yl)-ethylideneamino]- 1H), 7.10-7.07(m, 1H), 7.01-6.95(m,pyrrolidin-2-one 1H), 4.38(s, 2H), 3.49-3.44(m, 2H), 2.58(s, 3H),2.46-2.40(m, 2H), 1.93-1.88(m, 2H) 340 1-[2-(2-Chloro-4-fluoro- ¹HNMR(CDCl₃) δ 8.62-8.61(m, 1H), 7.90-7.87(m,phenyl)-1-(6-methyl-pyridin-2- 1H), 7.60-7.55(m, 1H), 7.30-7.25(m,yl)-ethylideneamino]- 1H), 7.14-7.02(m, 1H), 6.86-6.80(m,pyrrolidin-2-one 1H), 4.44(s, 2H), 3.52-3.47(m, 2H), 2.52(s, 3H),2.42-2.36(m, 2H), 1.94-1.86(m, 2H) 341 1-[2-(4-Fluoro-3- ¹H NMR(CDCl₃) δ7.89-7.87(m, 1H), 7.62-7.53(m, trifluoromethyl-phenyl)-1-(6- 2H),7.45-7.41(m, 1H), 7.28-7.19(m, methyl-pyridin-2-yl)- 1H), 7.16-7.01(m,1H), 4.43(s, 2H), ethylideneamino]-pyrrolidin-2- 3.52-3.47(m, 2H),2.56(s, 3H), 2.46-2.41(m, one 2H), 1.98-1.90(m, 2H) 3421-[1-(6-Methyl-pyridin-2-yl)-2- ¹H NMR(CDCl₃) δ 8.63-8.61(m, 1H),7.91-7.88 (2,4,5-trifluorophenyl)- 7.88(m, 1H), 7.65-7.58(m, 1H),7.31-7.14(m, ethylideneamino]-pyrrolidin-2- 1H), 6.87-6.78(m, 1H),4.32(s, 2H), one 3.59-3.55(m, 2H), 2.55(s, 3H), 2.50-2.44(m, 2H),2.04-1.99(m, 2H) 343 1-[2-(8-Fluoro-quinolin-4-yl)- ¹H NMR(CDCl₃) δ8.80-8.75(m, 1H), 7.95-7.85(m, 1-(6-methyl-pyridin-2-yl)- 2H),7.70-7.60(m, 1H), 7.45-7.20(m, ethylideneamino]-pyrrolidin-2- 4H),4.90(s, 2H), 3.10-3.00(m, 2H), one 2.20-2.15(m, 2H), 1.48-1.35(m, 2H).344 1-[2-(7-Bromo-quinolin-4-yl)- ¹H NMR(CDCl₃) δ 8.72(m, 1H), 8.28(m,1-(6-methyl-pyridin-2-yl)- 1H), 8.00-7.90(m, 2H), 7.70-7.55(m, 2H),ethylideneamino]-pyrrolidin-2- 7.30-6.20(m, 2H), 4.90(s, 2H),3.10-3.00(m, one 2H), 2.52(s, 3H), 2.20-2.15(m, 2H), 1.48-1.35(m, 2H)345 1-[2-(6-Trifluoromethoxy- ¹H NMR(CDCl₃) δ 8.75(m, 1H), 8.22(m,quinolin-4-yl)-1-(6-methyl- 1H), 7.98(s, 1H), 7.86(m, 1H), 7.62(m, 1H),pyridin-2-yl)-ethylideneamino]- 7.53(m, 1H), 7.35(m, 1H), 7.20-7.10(m,pyrrolidin-2-one 1H), 4.82(s, 2H), 3.14(m, 2H), 2.52(s, 3H), 2.26(m,2H), 1.52(m, 2H) 346 1-[2-(7-Trifluoromethyl- ¹H NMR(CDCl₃) δ8.80-8.75(m, 1H), 8.35(s, quinolin-4-yl)-1-(6-methyl- 1H), 8.22-8.18(m,1H), 7.90-7.85(m, pyridin-2-yl)-ethylideneamino]- 1H), 7.65-7.52(m, 2H),7.25-7.10(m, 2H), pyrrolidin-2-one 4.90(s, 2H), 3.10-3.00(m, 2H),2.50(s, 3H), 2.20-2.15(m, 2H), 1.48-1.35(m, 2H) 3471-[2-(7-Methoxy-quinolin-4- ¹H NMR(CDCl₃) δ 8.62(m, 1H), 7.94(m,yl)-1-(6-methyl-pyridin-2-yl)- 2H), 7.62(m, 1H), 7.41(m, 1H), 7.21(m,ethylideneamino]-pyrrolidin-2- 1H), 7.12(m, 2H), 4.89(s, 2H), 3.94(s,3H), one 3.05(m, 2H), 2.55(s, 3H), 1.61(m, 2H), 1.37(m, 2H). 3481-[2-(7-Bromo-quinolin-4-yl)- ¹H NMR(CDCl₃) δ 8.72(d, J=4.5Hz, 1H),1-pyridin-2-yl- 8.60(d, J=4.5Hz, 1H), 8.30(d, J=2.0Hz,ethylideneamino]-pyrrolidin-2- 1H), 8.15(dd, J=7.8, 1.0Hz, 1H), 7.95(d,J=9.0Hz, one 1H), 7.80(dt, J=2.0, 7.8Hz, 1H), 7.58(dd, J=2.0, 9.0Hz,1H), 7.40(dd, J=4.5, 7.8Hz, 1H), 7.20(m, 1H), 4.90(s, 2H), 3.10(t,J=6.8Hz, 2H), 2.22(t, J=6.8Hz, 2H), 1.44(q, J=6.8Hz, 2H) 3491-[2-(2-Chloro-pyridin-4-yl)-1- ¹H NMR(CDCl₃) δ 8.63(m, 1H), 8.22(d,J=4.5Hz, pyridin-2-yl-ethylideneamino]- 1H), 8.11(m, 1H), 7.75(dd,J=7.0, pyrrolidin-2-one 2.0Hz, 1H), 7.36(m, 1H), 7.16(m, 1H), 7.07(m,1H), 4.45(s, 2H), 3.51(t, J=7.0Hz, 1H), 2.41(t, J=7.0Hz, 2H), 2.35(s,3H), 1.87(m, 2H) 350 5-Hydroxymethyl-1-[1-(6- ¹H NMR(CDCl₃): δ 8.65(d,J=4.5Hz, 1H), methyl-pyridin-2-yl)-2- 8.00-8.15(m, 2H), 7.80(d, J=9.0Hz,1H), quinolin-4-yl- 7.40-7.75(m, 3H), 7.20-7.35(m, 2H), 4.80-5.00(m,ethylideneamino]-pyrrolidin-2- 2H), 3.20-3.50(m, 2H), 3.10(dd, J=9.0,one 4.5Hz, 1H), 2.55(s, 3H), 2.10-2.40(m, 2H), 1.20-1.60(m, 2H) 3511-[2-(7-Bromo-quinolin-4-yl)- ¹H NMR(CDCl₃): δ 8.75(d, J=4.4Hz, 1H),1-(6-methyl-pyridin-2-yl)- 8.28(d, J=2.0Hz, 1H), 7.97(d, J=7.0Hz,ethylideneamino]-5- 1H), 7.88(d, J=6.0Hz, 1H), 7.15-7.75(m,hydroxymethyl-pyrrolidin-2- 4H), 4.95(d, J=15Hz, 1H), 4.85(d, J=15Hz,one 1H), 3.30-3.60(m, 2H), 3.10-3.21(m, 1H), 2.55(s, 3H), 2.05-2.40(m,2H), 1.30-1.70(m, 2H). 352 1-[1-(6-Chloro-pyridin-2-yl)-2- ¹HNMR(CDCl₃): δ 8.85(d, J=4.4Hz, 1H), quinolin-4-yl- 8.00-8.25(m, 3H),7.40-7.80(m, 3H), 7.05-7.35(m, ethylideneamino]-4-(4-fluoro- 6H),5.25(d, J=16.6Hz, 1H), 4.75(d, phenyl)-pyrrolidin-2-one J=16.6Hz, 1H),3.10-3.45(m, 2H), 2.70-2.95(m, 2H), 2.35-2.55(m, 1H) 353(S)-5-Benzyloxymethyl-1-[1- ¹H NMR(CDCl₃): δ 8.68(d, J=4.4Hz, 1H),(6-chloro-pyridin-2-yl)-2- 8.08(d, J=7.7Hz, 1H), 7.95-8.00(m, 2H),quinolin-4-yl- 7.62-7.71(m, 2H), 7.42-7.50(m, 1H), 7.15-7.38(m,ethylideneamino]-pyrrolidin-2- 7H), 4.82-4.86(m, 2H), 4.28(s, 2H), one3.42-3.50(m, 1H), 3.05-3.12(m, 2H), 2.32-2.44(m, 1H), 2.08-2.15(m, 1H),1.45-1.65(m, 2H) 354 (S)-5-Benzyloxymethyl-1-[2- ¹H NMR(CDCl₃): δ8.77(d, J=4.4Hz, 1H), (7-chloro-quinolin-4-yl)-1-(6- 8.01-8.11(m, 2H),7.15-7.88(m, 10H), 4.86(d, methyl-pyridin-2-yl)- J=2.9Hz, 2H),4.50-4.60(m, 1H), 4.33(d, ethylideneamino]-pyrrolidin-2- J=2.9Hz, 2H),3.70-3.90(m, 2H), 3.45-3.60(m, one 2H), 2.47(s, 3H), 2.15-2.42(m, 2H)355 4-{1-[1-(6-Methyl-pyridin-2- ¹H NMR(CDCl₃): δ 8.76(d, J=4.5Hz, 1H),yl)-2-quinolin-4-yl- 8.15(d, J=8.5Hz, 1H), 8.09(d, J=8.3Hz,ethylideneamino]-5-oxo- 1H), 7.97(d, J=7.9Hz, 1H), 7.85(d, J=8.3Hz,pyrrolidin-3-yl}-benzoic acid 1H), 7.50-7.75(m, 5H), 7.15-7.25(m, ethylester 1H), 6.93(d, J=8.3Hz, 2H), 5.24(d, J=16.6Hz, 1H), 4.72(d,J=16.6Hz, 1H), 4.35(q, J=7.1Hz, 2H), 3.35(t, J=8.8Hz, 1H), 3.16(t,J=8.8Hz, 1H), 2.51-2.78(m, 4H), 2.32(dd, J=9.2, 17.0Hz, 1H),1.45-1.55(m, 1H), 1.40(t, J=7.1Hz, 3H). 356 1-(Benzhydrylidene-amino)-3-MS ES⁺ m/e 355 (M + 1) benzyl-pyrrolidin-2-one 3571-(Benzhydrylidene-amino)-3- MS ES⁺ m/e 293 (M + 1)ethyl-pyrrolidin-2-one

Preparation 358(R)-5-Benzyloxymethyl-1-[2-(4-fluoro-phenyl)-1-(6-methyl-pyridin-2-yl)-ethylideneamino]-pyrrolidin-2-one

Boron trifluoride etherate (0.25 mL, 1.98 mmol) is added to a solutionof 2-(4-fluoro-phenyl)-1-(6-methyl-pyridin-2-yl)-ethanone (0.45 g, 1.98mmol) in tetrahydrofuran (6.6 mL) under nitrogen and stirred for 30 min.A solution of (R)-1-amino-5-benzyloxymethyl-pyrrolidin-2-one (0.43 g,1.98 mmol) in tetrahydrofuran (1.0 mL) is added and the resultingmixture is stirred for 1 h. The mixture is concentrated in vacuo and theresidue chromatographed on a SiO₂ column (30% ethyl acetate/hexanes) toyield the title compound, 380 mg (45%), as a yellow foam.

¹H NMR (CDCl₃): δ 7.81 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H),7.11-7.32 (m, 8H), 6.81 (td, J=8.7, 2.0 Hz, 2H), 4.45 (s, 2H), 4.30-4.43(m, 2H), 3.80 (m, 1H), 3.39-3.51 (m, 2H), 2.51-2.63 (m, 4H), 2.23-2.41(m, 1H), 1.86-2.04 (m, 2H).

Preparation 3594-(4-Chloro-phenyl)-1-[2-(4-fluoro-phenyl)-1-(6-methyl-pyridin-2-yl)-ethylideneamino]-pyrrolidin-2-one

A method similar to PREPARATION 358, except employing1-amino-4-(4-chloro-phenyl)-pyrrolidin-2-one (1.47 g, 7.0 mmol), is usedto yield the title compound, 1.56 g (53%), as a yellow foam.

¹H NMR (CDCl₃): δ 7.55-7.66 (m, 1H), 7.15-7.45 (m, 7H), 6.89-7.07 (m,3H), 4.61 (d, J=15.4 Hz, 1H), 4.28 (d, J=15.4 Hz, 1H), 3.54-3.71 (m,2H), 3.26-3.42 (m, 1H), 2.75-2.89 (m, 1H), 2.58 (s, 3H), 2.46-2.56 (m,1H).

Preparation 360(S)-5-Benzyloxymethyl-1-[2-(4-fluoro-phenyl)-1-(6-methyl-pyridin-2-yl)-ethylideneamino]-pyrrolidin-2-one

A mixture of (S)-1-amino-5-benzyloxymethyl-pyrrolidin-2-one (0.5 g, 2.27mmol) and 2-(4-fluoro-phenyl)-1-(6-methyl-pyridin-2-yl)-ethanone (0.52g, 2.27 mmol) in toluene (2.5 mL) in a round bottom flask equipped witha Dean-Stark apparatus is refluxed for 1 h. The mixture is concentratedin vacuo and the residue chromatographed on SiO₂ (40% ethylacetate/hexanes) to yield the title compound, 500 mg (52%), as a paleyellow oil.

¹H NMR (CDCl₃): δ 7.81 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H),7.11-7.32 (m, 8H), 6.81 (td, J=8.7, 2.0 Hz, 2H), 4.45 (s, 2H), 4.30-4.43(m, 2H), 3.80 (m, 1H), 3.39-3.51 (m, 2H), 2.51-2.63 (m, 4H), 2.23-2.41(m, 1H), 1.86-2.04 (m, 2H).

Preparation 3614-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-[3-(pyrimidin-2-ylsulfanyl)-propoxy]-quinoline

7-(3-Chloro-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline(0.060 g, 0.148 mmol), 2-mercaptopyrimidine (0.033 g, 0.296 mmol, 2.0equiv) and potassium iodide (0.010 g, 0.120 mmol, 0.80 equiv) arecombined in N,N-dimethylformamide (1.0 mL) and the reaction is heated at60° C. for 72 h. The mixture is placed on a 10 g SCX resin column. Theresin is washed sequentially with 9:1 dichloromethane: methanol (2×120mL), 4:1 dichloromethane: methanol (2 N ammonia) (2×125 mL), andmethanol (2 N ammonia) (125 mL). The ammonia washes are evaporated todryness and the residue is subjected to chromatography on silica gel (20g, 99:1 dichloromethane: methanol (2 N ammonia)) to yield 0.054 g (76%)of the desired product as a tan solid.

MS ES⁺ m/e 482 (M+1).

By a similar method the following compounds are prepared (unlessotherwise specified):

PREP # Product Name Physical Data 3627-[3-(1-Methyl-1H-imidazol-2-ylsulfanyl)-propoxy]-4-(2- MS ES⁺ m/epyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- 484 (M + 1)yl)-quinoline 3637-[3-(4-Chloro-phenylsulfanyl)-propoxy]-4-(2-pyridin-2- MS ES⁺ m/eyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- 514 (M + 1) yl)-quinoline 3644-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS ES⁺ m/e3-yl)-7-[3-(4-pyrimidin-2-yl-piperazin-1- 534 (M + 1)yl)-propoxy]-quinoline 3657-{3-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-propoxy}-4- MS ES⁺ m/e(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- 562 (M + 1)b]pyrazol-3-yl)-quinoline 366Pyridin-2-yl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H- MS ES⁺ m/epyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine 463 (M + 1)367 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS ES⁺ m/e3-yl)-7-[3-(pyridin-2-ylmethylsulfanyl)-propoxy]- 495 (M + 1) quinoline

Preparation 3682-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylicacid ethyl ester

A solution of (6-methyl-pyridin-2-yl)-propynoic acid ethyl ester (3 g,15.9 mmol) and 3a H-pyrrolidino[1,2-C]1,2,3-oxadiazolin-3-one (2 g, 15.9mmol) is heated in xylene (50 mL) at 150° C. for 48 h. The mixture iscooled and concentrated in vacuo. The crude residue is chromatographedon SiO₂ (ethyl acetate) to give the title compound, 1.6 g (37%), as abrown solid.

MS ES⁺ m/e 272 (M+1).

Preparation 3692-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylicacid

A solution of2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylicacid ethyl ester (1.6 g, 5.9 mmol) and 2 N sodium hydroxide (6 mL, 29mmol) in absolute ethanol (50 mL) is refluxed for 5 h. The mixture iscooled to room temperature and concentrated in vacuo. The residue issuspended in water and acidified to pH 5 with 1 N hydrochloric acid. Theaqueous solution is extracted three times with dichloromethane. Theorganic extracts are combined, dried (sodium sulfate), filtered, andconcentrated in vacuo to yield the title compound, 1.4 g (97%), as awhite solid.

MS ES⁻ m/e 242 (M−1).

Preparation 3703-Bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

A solution of2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylicacid (1.4 g, 5.8 mmol) in N,N-dimethylformamide (20 mL) is treated withN-bromosuccinamide (1 g, 5.6 mmol) and stirred at room temperature for16 h. The mixture is diluted with ethyl acetate and washed three timeswith water, once with brine, dried (sodium sulfate), filtered, andconcentrated in vacuo to yield the title compound, 1.5 g (94%), as lightyellow solid.

MS ES⁺ m/e 278 (M+1).

Preparation 3714-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylicacid

Lithium hydroxide monohydrate (0.65 g, 15.6 mmol) is added to a solutionof4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylicacid methyl ester (1.44 g, 3.89 mmol) in 2:1 tetrahydrofuran/water (30mL), stirred at room temperature for 18 h, and concentrated in vacuo.The residue is purified by SCX resin, (2 N ammonia in methanol), toyield the title compound, 1.22 g (88%), as a tan solid.

¹H NMR (DMSO-d₆): δ 8.91 (m, 1H), 8.55 (m, 1H), 7.48-7.85 (m, 7H), 7.41(m, 1H), 7.09 (m, 1H), 4.22 (m, 2H), 2.81 (m, 2H), 2.60 (m, 2H).

By a similar method the following compounds are prepared (unlessotherwise specified):

PREP # Product Name Physical Data 372 6-(3-Quinolin-4-yl-5,6-dihydro- MSES⁺ m/e 357 (M + 1) 4H-pyrrolo[1,2-b]pyrazol-2- yl)pyridine-2-carboxylicacid dihydrochloride 373 3-{4-[2-(6-Methyl-pyridin-2-yl)- ¹H NMR(CDCl₃)δ 5,6-dihydro-4H-pyrrolo[1,2- 8.85-8.79(m, 1H), 8.20(s,b]pyrazol-3-yl]-quinolin- 1H), 7.75-7.66(m, 7-yl}-propionic acid 1H),7.35-7.23(m, 3H), 1H), 4.41-4.28(m, 2H), 3.29-3.18(m, 2H), 2.90-2.76(m,4H), 2.75-2.60(m, 2H), 2.29(s, 3H)

Preparation 374(S)-6-Benzyloxymethyl-3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

A method similar to PREPARATION 360, except employing(8)-5-benzyloxymethyl-1-[2-(4-fluoro-phenyl)-1-(6-methyl-pyridin-2-yl)-ethylideneamino]-pyrrolidin-2-one(0.5 g, 1.16 mmol), is used to yield the title compound, 325 mg (68%),as pale brown oil.

¹H NMR (CDCl₃): δ 7.50 (t, J=8.8 Hz, 1H), 7.17-7.47 (m, 8H), 6.96-7.06(m, 3H), 4.61 (m, 1H), 4.50 (s, 2H), 3.98 (dd, J=9.8, 3.2 Hz, 1H), 3.87(dd, J=9.8, 5.6 Hz, 1H), 2.68-3.05 (m, 4H), 2.54 (s, 3H).

MS APCI⁺ m/e 414 (M+1).

Preparation 375 5-Chloromethyl-2,2-difluoro-benzo[1,3]dioxole

A solution of (2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanol (1.0 g, 5.32mmol) in carbon tetrachloride (10.6 mL) is added to polymer-supportedtriphenylphospine (3.5 g, 3 mmol/g, 10.6 mmol) at room temperature. Thereaction is heated for 3 h at 80° C., cooled to room temperature,filtered, and the solids washed with dichloromethane. The filtrate isconcentrated in vacuo to yield the title compound, 0.79 g (72%), as aclear, orange oil.

MS CI⁺ m/e 207 (M+1).

By the previous method the following compounds are essentially prepared(unless otherwise specified):

PREP # Product Name Physical Data 3764-[2-(6-Chloromethyl-pyridin-2-yl)- MS ES⁺ m/e 361 (M + 1).5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-3-yl]quinoline 3773-Chloromethyl-pyrrolidine-1- MS CI⁺ m/e 254 (M + 1) carboxylic acidbenzyl ester

Preparation 378 Methanesulfonic acid2-pyridin-2-yl-3-quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-ylmethylester

A solution of[2-(6-methyl-pyridin-2-yl)-3-quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-methanol(30 mg, 0.07 mmol) and 4-dimethylaminopyridine (catalytic) in pyridine(0.2 mL) is cooled to 0° C. and treated with methanesulfonyl chloride (8mL, 0.105 mmol) and stirred for 30 min. The mixture is stirred at roomtemperature for 30 min, diluted with ethyl acetate (20 mL), washed withwater and brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo to yield the title compound, 30 mg (86%,) as ayellow oil.

¹H NMR (CDCl₃): δ 8.90 (d, J=4.0 Hz, 1H), 8.45 (d, J=4.0 Hz, 1H), 8.15(d, J=8.5 Hz, 1H), 7.55-7.70 (m, 2H), 7.36-7.48 (m, 2H), 7.05-7.30 (m,3H), 4.80-4.90 (m, 2H), 4.65-4.75 (m, 1H), 2.65-3.05 (m, 7H).

By a similar method the following compounds are prepared (unlessotherwise specified):

PREP # Product Name Physical Data 379 (R)-Methanesulfonic acid 3- ¹HNMR(CDCl₃): δ 8.63(bs, 1H), (benzhydrylidene- 7.22-7.63(m, 15H),4.95-5.14(m, 1H), hydrazinocarbonyl)-1- 4.52-4.65(m, 2H), 3.68-3.73(m,2H), benzyloxymethyl-propyl ester 3.00-3.13(m, 5H), 2.05-2.28(m, 2H) 3804-[2-(Benzhydrylidene- ¹H NMR(CDCl₃): δ 8.32(s, 1H),hydrazinocarbonyl)-1- 8.02(d, J=8.3Hz, 2H), 7.17-7.57(m, 12H),methanesulfonyloxymethyl-ethyl] 4.49(dd, J=6.5, 1.9Hz, 2H), 4.36(q,J=7.1Hz, benzoic acid ethyl ester 2H), 3.67-3.90(m, 1H), 3.31-3.43(m,2H), 2.86(s, 3H), 1.38(t, J=7.1Hz, 3H) 381 Methanesulfonic acid 3- ¹HNMR(CDCl₃): δ 8.35(bs, 1H), (benzhydrylidene-hydrazino 7.22-7.61(m,10H), 4.20(s, 2H), 3.01(s, carbonyl)-2,2-dimethyl-propyl ester 3H),2.92(s, 2H), 1.18(s, 6H) 382 (S)-Methanesulfonic acid 3- ¹H NMR(CDCl₃):δ 8.63(bs, 1H), (benzhydrylidene- 7.22-7.63(m, 15H), 4.95-5.14(m, 1H),hydrazinocarbonyl)-1- 4.52-4.65(m, 2H), 3.68-3.73(m, 2H),benzyloxymethyl-propyl ester 3.00-3.13(m, 5H), 2.05-2.28(m, 2H) 383Methanesulfonic acid 3- ¹H NMR(CDCl₃): δ 8.32(bs, 1H), (benzhydrylidene-7.15-7.57(m, 14H), 4.41-4.52(m, 2H), hydrazinocarbonyl)-2-(4-chloro-3.71-3.81(m, 1H), 3.24-3.36(m, 2H), phenyl)-propyl ester 2.88(s, 3H) 384(R)-Methanesulfonic acid 3-(4- ¹H NMR(CDCl₃): δ 7.40-7.51(m, 1H),fluoro-phenyl)-2-(6-methyl-pyridin- 6.92-7.25(m, 6H), 4.58-4.79(m, 3H),2-yl)-5,6-dihydro-4H-pyrrolo[1,2- 2.81-3.18(m, 6H), 2.61-2.72(m, 1H),b]pyrazol-6-ylmethyl ester 2.54(s, 3H) 385 Methanesulfonic acid5-chloro- ¹H NMR(DMSO-d₆): δ 4.22(m, 2H), pentyl ester 3.53(m, 2H),2.95(s, 3H), 1.81(m, 4H), 1.55(m, 2H) 386 Methanesulfonic acidtetrahydro- ¹H NMR(DMSO-d₆): δ 4.21(m, 3H), furan-2-ylmethyl ester3.82(m, 2H), 3.05(s, 3H), 1.84-2.05(m, 3H), 1.68(m, 1H)

Preparation 3874-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-piperidine-1-carboxylicacid tert-butyl ester

To a suspension of4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol(0.27 g, 0.84 mmol) in N,N-dimethylformamide (15 mL) is added4-bromo-piperidine-1-carboxylic acid tert-butyl ester (0.29 mL, 2.28mmol) and cesium carbonate (1.5 g, 4.57 mmol. The mixture is heated at80° C. for 48 h and concentrated in vacuo. The residue is taken up indichloromethane, washed with water and brine, dried over sodium sulfate,and concentrated in vacuo. Purification by flash chromatography (SiO₂,7% methanol in dichloromethane) yields the title compound, 262 mg (61%,)as a yellow oil.

MS ES+ m/e 512 (M+1).

By the previous method the following compounds are essentially prepared(unless otherwise specified):

PREP # Product Name Physical Data 3884-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- MS ES+ m/e 560 pyrrolo[1,2-b](M + 1) pyrazol-3-yl)-quinolin-7-yloxy]- piperidine-1- carboxylic acidtert-butyl ester 389 7-(5-Chloro-pentyloxy)-4-(2-pyridin- MS APC⁺ m/e433 2-yl-5,6-dihydro-4H-pyrrolo[1,2- (M + 1). b]pyrazol-3-yl)-quinoline390 3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- MS APC⁺ m/e 546pyrrolo[1,2-b]pyrazol-3-yl)-quinolin- (M + 1)7-yloxymethyl]-pyrrolidine-1- carboxylic acid benzyl ester 391Dimethyl-{5-[4-(2-pyridin-2-yl-5,6- mp: 115-118° C.dihydro-4H-pyrrolo[1,2-b]pyrazol-3- MS APC⁺ m/e 424yl)-quinolin-7-yloxy]-pentyl}-amine (M + 1) 392Methyl-{5-[4-(2-pyridin-2-yl-5,6- MS APC⁺ m/e 428dihydro-4H-pyrrolo[1,2-b]pyrazol-3- (M + 1)yl)-quinolin-7-yloxy]-pentyl}-amine 3931,3-Bis-{3-[4-(2-pyridin-2-yl-5,6- MS APC⁺ m/e 872dihydro-4H-pyrrolo[1,2-b]pyrazol-3- (M + 1)yl)-quinolin-7-yloxy]-propyl}-1,3- dihydro-benzoimidazol-2-one

Preparation 3944-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-2-carboxylicacid ethyl ester and4-(3-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-quinoline-2-carboxylicacid ethyl ester

A mixture of 3a H-pyrrolidino[1,2-C]1,2,3-oxadiazolin-3-one (28 mg, 0.22mmol) and 4-pyridin-2-ylethynyl-quinoline-2-carboxylic acid ethyl ester(0.11 g, 0.33 mmol) in xylene (2.2 mL) is refluxed in an oil bath for 96h. The solvent is removed in vacuo and the residue chromatographed onSiO₂ (0 to 1% methanol in chloroform with 3 drops ammonium hydroxide per150 mL solvent) to yield 9.1 mg of regioisomer 1 and 28.6 mg ofregioisomer 2.

Regioisomer 1: ¹H NMR (CDCl₃) δ: 8.26 (d, 2h), 8.04 (s, 1H), 7.69 (d,1H), 7.63 (t, 1H), 7.39 (t, 1H), 7.35 (t, 1H), 7.25 (d, 1H), 6.79 (t,1H), 4.47 (quartet, 2H), 4.31 (t, 2H), 2.82 (m, 2H), 2.65 (quintet, 2H),1.40 (t, 3H); MS ES⁺ m/e 385 (M+1).

Regioisomer 2: ¹H NMR (CDCl₃) δ: 8.39 (d, 1H), 8.27 (d, 1H), 8.20 (s,1H), 7.90 (d, 1H), 7.65 (t, 1H), 7.37 (t, 1H), 7.18 (t, 1H), 6.57 (d,1H), 4.26 (t, 2H), 3.26 (t, 2H), 2.70 (quintet, 2H), 1.38 (t, 3H); MSES⁺ m/e 385 (M+1).

Preparation 3952-(2-Hydroxyethyl)-3-hydroxymethyl-5-pyridin-2-yl-4-quinolin-4-yl-pyrazole

To a solution of2-pyridin-2-yl-3-quinolin-4-yl-pyrazolo[5,1-c]morpholin-4-one (0.50 g,1.46 mmol) in tetrahydrofuran (20 mL) is added LiAlH₄ (0.50 g, 13.1mmol) at room temperature. The mixture is stirred for 2 h quenched with1 N sodium hydroxide solution, and partitioned between dichloromethaneand water. The organic portion is dried (sodium sulfate), filtered, andconcentrated in vacuo. The residue is chromatographed on SiO₂ (10%methanol/dichloromethane) to yield the title compound, 0.35 g (70%), asan off-white solid.

TOF MS ES+ exact mass calculated for C₂₀H₁₉N₄O₂ (p+1): m/z=347.1508.Found: 347.1496.

By the previous method the following compound is essentially prepared(unless otherwise specified):

PREP # Product Name Physical Data 396 (2,2-Difluoro-benzo[1,3]dioxol- ¹HNMR(DMSO-d₆): δ 7.18(s, 5-yl)-methanol 1H), 6.96(s, 2H), 4.61(m, 2H)

Preparation 397 3-Ethoxycarbonyl-5-pyridin-2-yl-4-quinolin-4-yl-pyrazole

A solution of 2-quinolin-4-yl-1-pyridin-2-yl ethanone (1.00 g, 4.0 mmol)and hydrazine monohydrate (1.0 mL) in ethanol (200 mL) is heated atreflux for 2 h. The mixture is concentrated in vacuo to dryness, theresidue dissolved in pyridine (50 mL), cooled to 0° C., and treated withethyl oxalyl chloride (0.60 mL, 5.4 mmol) dropwise over 20 min. Themixture is warmed to room temperature, stirred for 2 h, and heated atreflux for 3 h. The mixture is concentrated in vacuo and the residuepartitioned between dichloromethane and water. The organic portion isdried (sodium sulfate), filtered, and concentrated in vacuo to yield thetitle compound, 0.6 g (44%,) as a white solid which is crystallized fromether.

¹H NMR (CDCl₃): δ 12.43 (br s, 1H), 9.02 (d, J=5 Hz, 1H), 8.56 (br s,1H), 8.32 (d, J=7 Hz, 1H), 7.76 (t, J=7 Hz, 1H), 7.65 (d, J=8 Hz, 1H),7.46 (m, 2H), 7.33 (br s, 1H), 7.17 (t, J=7 Hz, 1H), 4.11 (m, 1H), 0.90(t, J=7 Hz, 1H). MS ES⁺ m/e 345.0 (M+1).

Preparation 398 5-Pyridin-2-yl-4-quinolin-4-yl-2H-pyrazol-3-ol

To a solution of (1-pyridin-2-yl-2-quinolin-4-yl-ethylidene)-hydrazine(2.0 g, 7.6 mmol) in pyridine (20 mL) at 0° C. is added ethylchloroformate (2 mL) dropwise. The mixture is warmed to room temperatureand stirred for 2 h. The solution is refluxed for 12 h and concentratedin vacuo. The residue is treated with dichloromethane/methanol and theprecipitate collected by vacuum filtration. The precipitate istriturated with ethanol to yield the title compound, 300 mg (13%), as awhite solid.

MS ES⁺ m/e 288.9 (M+1).

Preparation 399[2-Methyl-2-({4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carbonyl}-amino)-propyl]-carbamicacid tert-butyl ester

To a solution of4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylicacid (0.16 g, 0.43 mmol), (2-amino-2-methyl-propyl)-carbamic acidtert-butyl ester (0.09 g, 0.47 mmol), EDC (0.09 g, 0.47 mmol),1-hydroxybenzotriazole (0.06 g, 0.47 mmol) in dichloromethane (8.6 mL)is added N,N-diisopropylethylamine (0.25 mL, 1.29 mmol). The mixture isstirred at room temperature for 18 hand concentrated in vacuo. Theresidue is taken up in ethyl acetate, washed with water and saturatedaqueous sodium chloride, dried over sodium sulfate and concentrated invacuo. The residue is chromatographed on SiO₂(methanol/dichloromethane/2:98) to yield the title compound 0.21 g (91%)as a white solid.

¹H NMR (CDCl₃) δ 8.93-8.86 (m, 1H), 8.51 (s, 1H), 7.79 (s, 2H),7.39-7.23 (m, 2H), 7.08-7.00 (m, 1H), 6.93-6.85 (m, 1H), 5.32-5.20 (m,1H), 4.424.31 (m, 2H), 3.41-3.32 (m, 2H), 2.89-2.78 (m, 2H), 2.75-2.61(m, 2H), 2.26 (s, 3H), 1.54-1.41 (m, 15H).

By the previous method the following compounds is prepared (unlessotherwise specified):

PREP # Product Name Physical Data 400 6-tert-Butoxycarbonylamino-2-{[4-MS APC⁺ m/e 599 (M + 1) (2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- quinoline-7-carbonyl]-amino}- hexanoic acidmethyl ester

Preparation 4014-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-piperidine-1-carboxylicacid tert-butyl ester

To a suspension of4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol(0.27 g, 0.84 mmol) in N,N-dimethylformamide (15 mL) is added4-bromo-piperidine-1-carboxylic acid tert-butyl ester (0.29 mL, 2.28mmol) and cesium carbonate (1.5 g, 4.57 mmol). The mixture is heated at80° C. for 48 h and concentrated in vacuo. The residue is taken up indichloromethane, washed with water and saturated aqueous sodiumchloride, dried over sodium sulfate, and concentrated in vacuo. Theresidue is chromatographed on SiO₂ (7% methanol in dichloromethane) toyield the title compound, 262 mg (61%), as a yellow oil.

MS ES+ m/e 512 (M+1).

By the previous method the following compound is prepared (unlessotherwise specified):

PREP # Product Name Physical Data 4024-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- MS ES+ m/e 560 (M + 1)pyrrolo[1,2-b]-pyrazol-3-yl)- quinolin-7-yloxy]-piperidine-1- carboxylicacid tert-butyl ester

Preparation 403[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-aceticacid

To a solution of[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-aceticacid ethyl ester (250 mg, 0.6 mmol) in methanol (4 mL) at roomtemperature is added 1 N lithium hydroxide (1.2 mL, 1.2 mmol). Themixture is heated at 60° C. for 4 h. The mixture is cooled to roomtemperature and concentrated in vacuo. The residue is taken up in waterand acidified to pH=6 with 1 N hydrochloric acid. The aqueous solutionis extracted with dichloromethane 5 times. The combined organic extractsare dried (sodium sulfate), filtered, and concentrated in vacuo to yieldthe title compound, 150 mg (65%), as an off white solid. MS ES⁻ m/e 385(M−1).

Preparation 4044-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-(tetrahydro-furan-2-ylmethoxy)-quinoline

A mixture of methanesulfonic acid tetrahydro-furan-2-ylmethyl ester(0.70 g, 3.66 mmol),4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol(400 mg, 1.22 mmol), and cesium carbonate (2.38 g, 7.32 mmol) inN,N-dimethylformamide (2.5 mL) is heated at 60° C. for 42 h. The mixtureis concentrated in vacuo and the residue chromatographed to yield thetitle compound, 79 mg (15%), as a tan solid.

MS APC⁺ m/e 413 (M+1).

By the previous method the following compounds is prepared. Unlessotherwise specified.

Product Physical PREP # (Chemical Name) Data 4051,5-Bis-(4-(2-pyridin-2-yl-5,6-dihydro-4H- mp: 154-156° C.pyrrolo[1,2-b]pyrazol-3-yl)-quinolin- MS APC⁺ m/e 7-oxy)-pentane 725(M + 1)

EXAMPLE 16-Bromo-4-(2-pyridin-2-3,1-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline

To a suspension of hexane-washed sodium hydride (60% dispersion inmineral oil, 347 mg, 50 mmol) in N,N-dimethylformamide (20 mL) is added1-[2-(6-bromo-quinolin-4-yl)-1-pyridin-2-yl-ethylideneamino]-pyrrolidin-2-one(2.2 g, 5.37 mmol). The resulting mixture is heated at 80-85° C. undernitrogen atmosphere for 18 h. The reaction is adjusted to pH 2 andneutralized with solid sodium carbonate. The product is extracted withethyl acetate, dried over sodium sulfate, and concentrated in vacuo. Theresidue is chromatographed on SiO₂ (dichloromethane to 2%methanol/dichloromethane) to yield a colorless solid, 1.145 g (54%).

MS ES⁺ m/e 391.2 & 393.2 (M+1).

By the above method, the following compounds are prepared (unlessotherwise specified):

Product EXAMPLE # (Chemical Name) Physical Data 23-Pyridin-4-yl-2-pyridin-2-yl-5,6-dihydro- MS ES⁺ m/e 262.3 (M + 1)4H-pyrrolo[1,2-b]pyrazole 3 2-(6-Methyl-pyridin-2-yl)-3-p-tolyl-5,6- TOFMS ES⁺ exact mass dihydro-4H-pyrrolo[1,2-b]pyrazole calculated forC₁₉H₂₀N₃ (p + 1): m/z = 290.1657 Found: 290.1667 44-[3-(6-Methyl-pyridin-2-yl)-5,6-dihydro- TOF MS ES⁺ exact mass4H-pyrrolo[1,2-b]pyrazol-2-yl]-quinoline calculated for C₂₁H₁₉N₄ (p +1): m/z = 327.1609. Found: 327.1628 52-(6-Methyl]-pyridin-2-yl)-3-naphthalen-1- TOF MS ES⁺ exact massyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole calculated for C₂₂H₂₀N₃ (p +1): m/z = 326.1657. Found: 326.1666 62-(6-Methylpyridin-2-yl)-3-pyridin-3-yl-5,6- TOF MS ES⁺ exact massdihydro-4H-pyrrolo[1,2-b]pyrazole calculated for C₁₇H₁₇N₄ (p + 1): m/z =277.1453. Found: 277.1452 7 4-[5-(4-Fluorophenyl)-2-(6-methyl-pyridin MSAPCI⁺ m/e 421 (M + 1). 2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline 8 3-(4-Fluor-naphthalen-1-yl)-2-(6-methyl- TOF MS ES⁺exact mass pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- calculated forC₂₂H₁₉FN₃ b]pyrazole (p + 1): m/z = 344.1563. Found: 344.1548 93-(3,4-Difluorophenyl)-2-(6-methyl-pyridin- TOF MS ES⁺ exact mass2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole calculated for C₁₈H₁₆F₂N₃(p + 1): m/z = 312.1312. Found: 312.1309 101-[2-(4-Methanesulfonyl-phenyl)-1-(6- TOF MS ES⁺ exact massmethyl-pyridin-2-yl)-ethylideneamino]- calculated for C₁₉H₂₀N₃O₂Spyrrolidin-2-one (p + 1): m/z = 354.1276. Found: 354.1281 117-Methoxy-4-(2-pyridin-2-yl-5,6-dihydro- TOF MS ES⁺ exact mass4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline calculated for C₂₁H₁₉N₄O (p +1): m/z = 343.1559. Found: 343.1574 127-Benzyloxy-6-methoxy-4-(2-pyridin-2-yl- TOF MS ES⁺ exact mass5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- calculated for C₂₈H₂₅N₄O₂quinoline (p + 1): m/z = 449.1978. Found: 449.1994 136-(2-Pyridin-2-yl-5,6-dihydro-4H- MS ES⁺ m/e 313 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 146-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro- MS ES⁺ m/e 327 (M + 1)4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline 153-Naphthalen-2-yl-2-pyridin-2-yl-5,6- MS ES⁺ m/e 312 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazole 162-(6-Methyl-pyridin-2-yl)-3-naphthalen-2- MS ES⁺ m/e 326 (M + 1)yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 173-(4-Fluoro-phenyl)-2-(6-trifluoromethyl- MS ES⁺ m/e 348 (M + 1)pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole 184-(Quinolin-4-yl)-3-(5-fluoropyridin-2-yl)- mp 62-66° C.; MS ES⁺ m/e5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 331 (M + 1) 194-(7-Bromoquinolin-4-yl)-3- mp 214-216° C.; MS ES⁺ m/e(pyridin-2-yl)-5,6-dihydro-4H- 391 (M + 1), 393 (M + 3)pyrrolo[1,2-b]pyrazole 20 (Quinolin-4-yl)-3-(2,4-difluorophenyl)-5,6- mp76-83° C.; MS ES⁺ m/e dihydro-4H-pyrrolo[1,2-b]pyrazole 348 (M + 1) 214-(2-Pyrazin-2-yl-5,6-dihydro-4H- MS (CI, methane) m/e 314pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (M + 1). 224-(5-Methyl-2-pyridin-2-yl-5,6-dihydro-4H- MS APCI+ m/e 327 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 236-Bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6- MS APCI⁺ m/e 405/407dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- (M + 1). quinoline 244-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro- MS APCI+ m/e 395 (M + 1)4H-pyrrolo[1,2-b]pyrazol-3-yl]-6- trifluoromethyl-quinoline 253-(3-Chloro-4-fluoro-phenyl)-2-(6-methyl- MS (CI, methane) 328pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- (M + 1) b]pyrazole 263-(2-Chloro-4-fluoro-phenyl)-2-(6-methyl- MS (CI, methane) 328pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- (M + 1) b]pyrazole 273-(4-Fluoro-3-trifluoromethyl-phenyl)-2-(6- MS (CI, methane) 362methyl-pyridin-2-yl)-5,6-dihydro-4H- (M + 1) pyrrolo[1,2-b]pyrazole 282-(6-Methyl-pyridin-2-yl)-3-(2,4,5-trifluoro- MS (CI, methane) 330phenyl)-5,6-dihydro-4H-pyrrolo[1,2- (M + 1) b]pyrazole 298-Fluoro-4-[2-(6-methyl-pyridin-2-yl)-5,6- MS APCI+ m/e 345 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline 307-Bromo-4-[2-(6-methyl-pyridin-2-yl)- MS APCI+ m/e 405/4075,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- (M + 1) yl]-quinoline 314-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro- MS APCI+ m/e 411 (M + 1)4H-pyrrolo[1,2-b]pyrazol-3-yl]-6- trifluoromethoxy-quinoline 324-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro- MS APCI+ m/e 395 (M + 1)4H-pyrrolo[1,2-b]pyrazol-3-yl]-7- trifluoromethyl-quinoline 337-Methoxy-4-[2-(6-methyl-pyridin-2-yl)- MS APCI+ m/e 357 (M + 1)5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline 343-(2-Chloro-pyridin-4-yl)-2-pyridin-2-yl- MS APCI⁺ m/e 297 (M + 1)5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 35[2-(6-Methyl-pyridin-2-yl)-3-quinolin-4-yl- MS APCI⁺ m/e 357 (M + 1)5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazol-6-yl]-methanol 36[3-(7-Bromo-quinolin-4-yl)-2-(6-methyl- MS APCI⁺ m/e 435/437pyridin-2-yl)-5,6- (M + 1) dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-methanol 37 4-[2-(6-Chloro-pyridin-2-yl)-5-(4- MS APCI⁺ m/e 441 (M + 1)fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-3-yl]-quinoline 384-[2-(6-Ethoxy-pyridin-2-yl)-5-(4-fluoro- MS APCI⁺ m/e 451 (M + 1)phenyl)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-3-yl]-quinoline 39(S)-4-[6-Benzyloxymethyl-2-(6-methyl- MS APCI⁺ m/e 481 (M + 1).pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-7-chloro-quinoline 40(S)-4-[6-Benzyloxymethyl-2-(6-chloro- MS APCI⁺ m/e 467 (M + 1).pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-3-yl]-quinoline 414-[2-(6-Methyl-pyridin-2-yl)-3-quinolin-4- MS APCI+ m/e 475 (M + 1).yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-5- yl]-benzoic acid ethyl ester42 3-(4-Fluoro-phenyl)-5,5-dimethyl-2-(6- MS APCI+ m/e 322 (M + 1).methyl-pyridin-2-yl)-5,6-dihydro-4H- mp: 117-118° C.pyrrolo[1,2-b]pyrazole 43 (R)-6-Benzyloxymethyl-3-(4-fluoro- MS APCI+m/e 414 (M + 1). phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 445-(4-Chloro-phenyl)-3-(4-fluoro-phenyl)-2- MS APCI+ m/e 404 (M + 1).(6-methyl-pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazole 454-[2-(3-Trifluoromethyl-phenyl)-4,5,6,7- MS APCI⁺ m/e 394 (M + 1).tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]- quinoline 464-[2-(4-Trifluoromethyl-phenyl)-4,5,6,7- MS APCI+ m/e 394 (M + 1)tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]- quinoline 474-[2-(4-Chlorophenyl)-4,5,6,7-tetrahydro- MS APCI⁺ m/e 360 (M + 1)pyrazolo[1,5-a]pyridin-3-yl]-quinoline 484-[2-(3-Chlorophenyl)-4,5,6,7-tetrahydro- MS APCI⁺ m/e 360 (M + 1)pyrazolo[1,5-alpyridin-3-y]-quinoline 494-[2-(3-Fluoro-5-trifluoromethyl-phenyl)- MS APCI⁺ m/e 398 (M + 1)5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline 504-[2-(3-Fluoro-5-trifluoromethyl-phenyl)- MS APCI⁺ m/e 412 (M + 1)4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3- yl]-quinoline 514-(2-Phenyl-4,5,6,7-tetrahydro- MS APCI⁺ m/e 326 (M + 1)pyrazolo[1,5-a]pyridin-3-yl)-quinoline 524-(2-Pyridin-2-yl-4,5,6,7-tetrahydro- MS APCI⁺ m/e 378 (M + 1)pyrazolo[1,5-a]pyridin-3-yl)- [1,10]phenanthroline 534-[2-(4-Fluoro-phenyl)-4,5,6,7-tetrahydro- MS APCI⁺ m/e 344 (M + 1)pyrazolo[1,5-a]pyridin-3-yl]-quinoline 544-[2-(3-Trifluoromethoxy-phenyl)-4,5,6,7- MS APCI⁺ m/e 410 (M + 1)tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]- quinoline 554-[2-(2-Fluoro-phenyl)-4,5,6,7-tetrahydro- APCI⁺ m/e 344 (M + 1)pyrazolo[1,5-a]pyridin-3-yl]-quinoline 564-(2-Quinolin-2-yl-4,5,6,7-tetrahydro- MS APCI⁺ m/e 377 (M + 1)pyrazolo[1,5-a]pyridin-3-yl)-quinoline 574-[2-(4-Ethyl-pyridin-2-yl)-4,5,6,7- MS APCI⁺ m/e 355 (M + 1)tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]- quinoline 584-(2-Quinolin-2-yl-5,6-dihydro-4H- MS APCI⁺ m/e 363 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 592-(3-Quinolin-4-yl-4,5,6,7-tetrahydro- MS APCI⁺ m/e 378 (M + 1)pyrazolo[1,5-a]pyridin-2-yl)- [1,8]naphthyridine 604-[5-(4-Fluoro-phenyl)-2-pyridin-2-yl-5,6- MS APCI⁺ m/e 407 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline 614-(6-Hydroxymethyl-2-pyridin-2-yl-5,6- MS APCI⁺ m/e 343 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3yl)- quinoline 624-(3-Pyridin-2-yl-5,6-dihydro-4H- MS ES⁺ m/e 313 (M + 1)pyrrolo[1,2-b]pyrazol-2-yl)-quinoline 634-(4-Methyl-2-pyridin-2-yl-5,6-dihydro-4H- MS ES⁺ m/e 327 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 644-(5-Benzyl-2-pyridin-2-yl-5,6-dihydro-4H- MS APCI⁺ m/e 403 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 654-(5-Phenethyl-2-pyridin-2-yl-5,6-dihydro- MS APCI⁺ m/e 417.4 (M + 1)4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 664-(5-Phenyl-2-pyridin-2-yl-5,6-dihydro- MS APCI⁺ m/e 399 (M + 1)4Hpyrrob[1,2-b]pyrazol-3-yl)-quinoline 674-[2-(3-Trifluoromethylphenyl)-5,6- MS APCI⁺ m/e 380 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline 684-[2-(4-Trifluoromethyl-phenyl)-5,6- MS APCI⁺ m/e 380 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline 694-(2-Phenyl-5,6-dihydro-4H-pyrrolo[1,2- MS APCI⁺ m/e 312 (M + 1)b]pyrazol-3-yl)-quinoline 70 2-Chloro-4-(2-pyridin-2-yl-5,6-dihydro-4H-MS APCI⁺ m/e 347 (M + 1) pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 716,8-Dimethoxy-4-[2-(6-methyl-pyridin-2- MS APCI⁺ m/e 387 (M + 1)yl)-5,6-dihydro-4H-pyrrolo[1,2b]pyrazol-3- yl]-quinoline 724-[2-(6-Bromo-pyridin-2-yl)-5,6-dihydro- MS calcd. 391; MS (M + 1)4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline 391,393 736,8-Dimethoxy-4-[2-pyridin-2-yl-5,6- MS APCI⁺ m/e 373 (M + 1)dihydro-4H-pyrrolo[1,2b]pyrazol-3-yl]- quinoline 743-(4-Fluorophenyl)-2-pyridin-2-yl-5,6- MS ES⁺ m/e 280.1 (M + 1).dihydro-4H-pyrrolo[1,2-b]pyrazole 753-(4-Methoxy-phenyl)-2-pyridin-2-yl-5,6- TOF MS ES⁺ exact massdihydro-4H-pyrrolo[1,2-b]pyrazole calculated for C₁₈H₁₈N_(3O) (p + 1):m/z 292.1450. Found: 292.1466. 763-(4-Fluorophenyl)-2-(6-methylpyridin-2- TOF MS ES⁺ exact massyl)-5,6-dihydro-4H-pyrrolo[1,2- calculated for C₁₈H₁₇N₃F b]pyrazole (p +1): m/z 294.1407. Found: 294.1416. 773-(4-Methoxyphenyl)-2-(6-methylpyridin-2- TOF MS ES⁺ exact massyl)-5,6-dihydro-4H-pyrrolo[1,2- calculated for C₁₉H₂₀N_(3O) b]pyrazole(p + 1): m/z 306.1606. Found: 306.1584. 784-(2-Thiophen-2-yl-5,6-dihydro-4H- TOF MS ES⁺ exact masspyrrolo[1,2-b]pyrazol-3-yl)quinoline calculated for C₁₉H₁₆N₃S (p + 1):m/z = 318.1065 Found: 318.1051 794-[2-(6-Propylpyridin-2-yl)-5,6-dihydro- TOF MS ES⁺ exact mass4H-pyrrolo[1,2-b]pyrazol-3-yl]- calculated for C₂₃H₂₃N₄ quinoline (p +1): m/z 355.1923 Found: 355.1909 804-[2-(6-Isopropylpyridin-2-yl)-5,6-dihydro- TOF MS ES⁺ exact mass4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline calculated for C₂₃H₂₃N₄ (p + 1):m/z 355.1923 Found: 355.1912 814-[2-(6-Ethyl-pyridin-2-yl)-5,6-dihydro-4H- TOF MS ES⁺ exact masspyrrolo[1,2-b]pyrazol-3-yl]quinoline calculated for C₂₂H₂₁N₄ (p + 1):m/z 341.1766 Found: 341.1766 824-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro- MS ES⁺ m/e 327 (M + 1)4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline 834-[2-(3-Fluorophenyl)-5,6-dihydro-4H- MS APCI⁺ m/e 330 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl]-quinoline 844-[2-(2-Fluoro-phenyl)-5,6-dihydro-4H- MS APCI⁺ m/e 330 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl]-quinoline 854-[2-(4-Fluoro-phenyl)-5,6-dihydro-4H- MS APCI⁺ m/e 330 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl]-quinoline 864-[2-(3-Trifluoromethoxy-phenyl)-5,6- MS APCI⁺ m/e 396 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline 874-[2-(4-Chloro-pyridin-2-yl)-5,6-dihydro- MS APCI⁺ m/e 347 (M + 1)4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline 884-[2-(4-Fluoro-3-trifluoromethyl-phenyl)- MS APCI⁺ m/e 398.3 (M + 1)5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- yl]quinoline 894-[2-(2-Fluoro-3-trifluoromethyl-phenyl)- MS APCI⁺ m/e 398.1 (M + 1)5,6-dihydro-4H-pyrrolo[1,2-b]-pyrazol-3- yl]-quinoline 904-[5-(3-Methoxy-phenyl)-2-pyridin-2-yl- MS APCI⁺ m/e 419 (M + 1)5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline 914-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-5- MS APCI⁺ m/e 504 (M + 1)(3-methoxy-phenyl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl]-quinoline92 3-(7-Chloro-quinolin-4-yl)-2-(6- mp 178-182° C.methylpyridin-2-yl)-5,6-dihydro-4H- MS ES⁺ m/e 361 (M + 1)pyrrolo[1,2-b]pyrazole 93 3-(7-Ethoxyquinolin-4-yl)-2-(6- mp 164-166° C.methylpyridin-2-yl)-5,6-dihydro-4H- MS ES⁺ m/e 371 (M + 1), 372pyrrolo[1,2-b]pyrazole (M + 2) 94 6-(3-Quinolin-4-yl-5,6-dihydro-4H- ¹HNMR(DMSO-d₆) δ: 2.65 pyrrolo[1,2-b]pyrazol-2-yl)-pyridine-2- (quintet,2H), 2.89(m, 2H), carboxylic acid hydrochloride 4.33(t, 2H), 7.59(t,2H), 7.72(d, 1H), 7.84(d, 1H), 7.85-8.00(m, 2H), 8.06(d, 1H), 8.22(m,1H), 8.40(d, 1H), 9.11(d, 1H) 956,7-Difluoro-4-[2-(6-methyl-pyridin-2-yl)- ESIMS m/e 363 (M ++ 1)5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- yl]-quinoline 966,7-Dimethoxy-4-[2-(6-methyl-pyridin-2- MS ES⁺ m/e 387 (M + 1)yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- 3-yl]-quinoline 974-[2-(6-Ch,6-dihydro-4H-pyrrolo loro- MS Calcd. 346; MS (APCI)pyridin-2-yl)-5[1,2-b]pyrazol-3-yl]- (M + 1) 347 quinoline 986-(3-Quinolin-4-yl-5,6-dihydro-4H- MS ES⁺ m/e 371 (M + 1)pyrrolo[1,2-b]pyrazol-2-yl)pyridine-2- carboxylic acid methyl ester 994-(7-Chloroquinolin-4-yl)-3-(pyridin-2-yl)- mp 208-211° C.5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole C,68.67; H, 4.55; N, 15.50; Found:C, 68.96; H, 4.30; N, 15.28 100 (4-(2-Furan-2-yl-5,6-dihydro-4H- TOF MSexact mass pyrrolo[1,2-b]pyrazol-3-yl)-quinoline calculated forC₁₉H₁₆N_(3O) (p + 1): m/z = 302.1293 Found: 302.1312 1013-{4-[2-(6-Methyl-pyridin-2-yl)-5,6- MS APCI+ m/e 411 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinolin-6-yl}-acrylic acidmethyl ester 102 4-[2-(2-Methyl-thiazol-4-yl)-5,6-dihydro- ES MS 333.4(M + 1) 4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline 1033-(4-Fluoro-phenyl)-2-(2-methyl-thiazol-4- MS (ES) m/e 300.4 (M + 1)yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 1044-[2-(2-Methyl-2H-pyrazol-3-yl)-5,6- MS (ES) m/e 316.4 (M⁺)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline 1054-(2-thiazol-2-yl-5,6-dihydro-4H- MS (ES) m/e 319 (M⁺)pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 1064-[2-(1-methyl-1H-imidazol-2-yl)-5,6- MS (ES) m/e 316 (M⁺)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline 1076,7-Dichloro-4-[2-(6-methyl-pyridin-2-yl)- MS ES⁺ m/e 395 (M + 1)5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- yl]-quinoline 108(S)-6-Benzyloxymethyl-3-(4-fluoro- MS CI⁺ m/e 414 (M + 1)phenyl)-2-(6-methyl-pyridin-2-yl)-5,6- dihydro-4H-pyrrolo[1,2-b]pyrazole

EXAMPLE 1093-Benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

A mixture of3-bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(99 mg, 0.36 mmol), 3,4-methylenedioxyphenylboronic acid (65 mg, 0.39mmol), (PPh₃)₄Pd (20 mg, 0.02 mmol), 1 N aqueous sodium carbonatesolution (500 μL, 0.5 mmol) in toluene (5 mL) and methanol (1 mL) ispurged with argon for 10 min and heated at 80° C. under nitrogen for 30h. The mixture is cooled and partitioned between water and ethylacetate, and the organic portion washed with water and brine, dried(sodium sulfate), filtered, and concentrated in vacuo. The crude residueis chromatographed on SiO₂ (ethyl acetate) to yield the title compound,10 mg (9%), as a yellow solid.

MS ES⁺ m/e 320 (M+1).

By the above method the following compounds are prepared (unlessotherwise specified):

Product EXAMPLE # (Chemical Name) Physical Data 1106-(4-Fluoro-phenyl)-4-[2-(6-methyl-pyridin-2-yl)- MS APCI+ m/e 4215,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- (M + 1) quinoline 1116-Benzo[1,3]dioxol-5-yl-4-[2-(6-methyl- MS APCI+ m/e 447pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- (M + 1)b]pyrazol-3-yl]-quinoline 1124-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI+ m/e 409pyrrolo[1,2-b]pyrazol-3-yl]-6-thiophen-2-yl- (M + 1) quinoline 1134-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI+ m/e 403pyrrolo[1,2-b]pyrazol-3-yl]-6-phenyl-quinoline (M + 1) 1148-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS (ES) m/epyrrolo[1,2-b]pyrazol-3-yl]-quinoline 327 (M⁺) 1153-Benzo[b]thiophen-2-yl-2-(6-methyl-pyridin- MS (ES) m/e2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 332 (M⁺)

EXAMPLE 1164-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-6-carboxylicacid methyl ester

To a mixture of sodium acetate (0.84 g, 10.2 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II):CH₂Cl₂ (42mg, 0.05 mmol) in methanol (40 mL) is added6-bromo-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline(1.0 g, 2.56 mmol). The mixture is heated at 90° C. under 68 psi carbonmonoxide for 24 h. The mixture is cooled, filtered, and concentrated invacuo. The product is partitioned between ethyl acetate and: water. Theorganic layer is dried over sodium sulfate and concentrated in vacuo.The residue is chromatographed on SiO₂ (dichloromethane to 2%methanol/dichloromethane) to yield a solid, 918 mg (97%).

MS ES⁺ m/e 371.2 (M+1).

By the above method, the following compounds are prepared (unlessotherwise specified):

Product Physical EXAMPLE # (Chemical Name) Data 1174-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- MS APCI⁺b]pyrazol-3-yl]-quinoline-6-carboxylic acid methyl ester m/e 385 (M + 1)118 4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- MS APCI⁺b]pyrazol-3-yl]-quinoline-7-carboxylic acid methyl ester m/e 385 (M + 1)119 4-[2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- MS APCI⁺yl]-quinoline-7-carboxylic acid methyl ester m/e 371 (M + 1)

EXAMPLE 120 2-Pyridin-2-yl-3-quinolin-4-yl-pyrazolo[5,1-c]morpholine

To a solution of2-(2-hydroxyethyl)-3-hydroxymethyl-5-pyridin-2-yl-4-quinoline-4-yl-pyrazole,(0.10 g, 0.29 mmol) in tetrahydrofuran (10 mL) cooled at 0° C. is addedNaH (0.04 g, 50% in mineral oil). The mixture is stirred for 2 h at roomtemperature and methanesulfonyl chloride (0.065 g, 0.57 mmol) is addeddropwise over 30 min. The reaction is quenched with water and extractedinto ethyl acetate. The organic layer is washed with water, dried(sodium sulfate), filtered, and concentrated in vacuo. The residue ischromatographed on SiO₂ (10% methanol/dichloromethane) to yield thetitle compound, 31 mg (33%), as a white solid.

TOF MS ES⁺ exact mass calculated for C₂₀H₁₆N₄O (p+1): m/z=329.1402.Found: 329.1409.

EXAMPLE 1212-Pyridin-2-yl-3-quinolin-4-yl-pyrazolo[5,1-c]morpholin-4-one

A mixture of 3-ethoxycarbonyl-5-pyridin-2-yl-4-quinolin-4-yl-pyrazole(0.35 g, 1.00 mmol), 2-bromoethanol (0.15 g, 1.12 mmol), and cesiumcarbonate (0.50 g, 1.5 mmol) in N,N-dimethylformamide (20 mL) is heatedat 60° C. for 2 h. The mixture is cooled to room temperature and pouredinto ethyl acetate (60 mL). The organic portion is washed with water,dried (sodium sulfate), filtered, and concentrated in vacuo. The residueis chromatographed on SiO₂ (ethyl acetate/hexane) to yield the titlecompound, 110 mg (32%).

TOF MS ES⁺ exact mass calculated for C₂₀H₁₅N₄O₂ (p+1): m/z=343.1195.Found: 343.1179.

EXAMPLE 122 5Dimethyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine

A solution of7-(3-chloro-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline(54 mg, 0.13 mmol), sodium iodide (5 mg, 0.03 mmol), and 2 Ndimethylamine in tetrahydrofuran (3 mL, 6 mmol) in N,N-dimethylformamide(5 mL) is heated at 100° C. for 48 h. The mixture is cooled andconcentrated in vacuo. The residue is chromatographed on SiO₂ (100%ethyl acetate to 10% methanol in ethyl acetate) to yield the titlecompound, 41 mg (74%), as a brown solid.

TOF MS ES⁺ exact mass calculated for C₂₅H₂₈N₅O (p+1): m/z=414.2294.Found: 414.2313.

By the above method the following compounds are prepared (unlessotherwise specified):

Product EXAMPLE # (Chemical Name) Physical Data 123{3-[6-Methoxy-4-(2-pyridin-2-yl-5,6-dihydro- TOF MS ES⁺ exact mass4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7- calculated for C₂₆H₃₀N₅O₂yloxy]-propyl}-dimethyl-amine (p + 1): m/z = 444.2399 Found: 444.2391124 Cyclopropylmethyl-propyl-{3-[4-(2-pyridin-2- TOF MS ES⁺ exact massyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- calculated for C₃₀H₃₆N₅Oyl)-quinolin-7-yloxy]-propyl}-amine (p + 1): m/z = 482.2920 Found:482.2934 125 Diethyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H- TOF MS ES⁺exact mass pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]- calculated forC₃₇H₃₂N₅O propyl}-amine (p + 1): m/z = 442.2607 Found: 442.2609 126Ethyl-methyl-{3-[4-(2-pyridin-2-yl-5,6- TOF MS ES⁺ exact massdihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- calculated for C₂₆H₃₀N₅Oquinolin-7-yloxy]-propyl}-amine (p + 1): m/z = 428.2450 Found: 428.2470127 3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- TOF MS ES⁺ exact masspyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]- calculated for C₂₃H₂₄N₅Opropylamine (p + 1): m/z = 386.1981 Found: 386.1994 1287-[3-(4-Methyl-piperazin-1-yl)-propoxy]-4-(2- TOF MS ES⁺ exact masspyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- calculated for C₂₈H₃₃N₆Ob]pyrazol-3-yl)-quinoline (p + 1): m/z = 469.2716 Found: 469.2735 129Benzyl-methyl-{3-[4-(2-pyridin-2-yl-5,6- TOF MS ES⁺ exact massdihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- calculated for C₃₁H₃₂N₅Oquinolin-7-yloxy]-propyl}-amine (p + 1): m/z = 490.2607 Found: 490.2629130 7-(3-Piperidin-1-yl-propoxy)-4-(2-pyridin-2- TOF MS ES⁺ exact massyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- calculated for C₂₈H₃₂N₅Oyl)-quinoline (p + 1) m/z = 454.2607 Found: 454.2602 1314-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- TOF MS ES⁺ exact massb]pyrazol-3-yl)-7-(3-pyrrolidin-1-yl-propoxy)- calculated for C₂₇H₃₀N₅Oquinoline (p + 1): m/z = 440.2450 Found: 440.2468 1327-(3-Azepan-1-yl-propoxy)-4-(2-pyridin-2-yl- TOF MS ES⁺ exact mass5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- calculated for C₂₉H₃₄N₅Oquinoline (p + 1): m/z = 468.2763 Found: 468.2762 1337-(3-Imidazol-1-yl-propoxy)-4-(2-pyridin-2- TOF MS ES⁺ exact massyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- calculated for C₂₆H₂₅N₆Oyl)-quinoline (p + 1): m/z = 437.2090 Found: 437.2096 1347-(3-Pyrazol-1-yl-propoxy)-4-(2-pyridin-2-yl- MS ES⁺ m/e 437 (M + 1)5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- quinoline 1351′-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- TOF MS ES⁺ exact masspyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]- calculated for C₃₃H₄₁N₆Opropyl}-[1,4′]bipiperidinyl (p + 1): m/z = 537.3342 Found: 537.3321 136Cyclopropyl-(1-methyl-piperidin-4-yl)-{3-[4- MS ES⁺ m/e 523 (M + 1)(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}- amine 1374-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/e 438 (M + 1)b]pyrazol-3-yl)-7-(3-[1,2,3]triazol-1-yl- propoxy)-quinoline 138Dimethyl-(3-{4-[2-(6-methyl-pyridin-2-yl)- TOF MS ES⁺ exact mass5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- calculated for C₂₆H₃₀N₅Oquinolin-7-yloxy}-propyl)-amine (p + 1): m/z = 428.2450 Found: 428.2464139 Diethyl-(3-{4-[2-(6-methyl-pyridin-2-yl)-5,6- TOF MS ES⁺ exact massdihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- calculated for C₂₈H₃₄N₅Oquinolin-7-yloxy}-propyl)-amine (p + 1): m/z = 456.2763 Found: 456.2785140 Cyclopropylmethyl-(3-{4-[2-(6-methyl- TOF MS ES⁺ exact masspyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- calculated for C₃₁H₃₈N₅Ob]pyrazol-3-yl]-quinolin-7-yloxy}-propyl)- (p + 1): propyl-amine m/z =496.3076 Found: 496.3094 141 Ethyl-methyl-(3-{4-[2-(6-methyl-pyridin-2-TOF MS ES⁺ exact mass yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-calculated for C₂₇H₃₂N₅O yl]-quinolin-7-yloxy}-propyl)-amine (p + 1):m/z = 442.2607 Found: 442.2615 142Dimethyl-{2-[4-(2-pyridin-2-yl-5,6-dihydro- MS ES⁺ m/e 400 (M + 1)4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7- yloxy]-ethyl}-amine 143Diethyl-{2-[4-(2-pyridin-2-yl-5,6-dihydro-4H- MS ES⁺ m/e 428 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]- ethyl}-amine 1447-(2-Piperidin-1-yl-ethoxy)-4-(2-pyridin-2-yl- MS ES⁺ m/e 440 (M + 1)5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- quinoline 145Ethyl-methyl-{2-[4-(2-pyridin-2-yl-5,6- MS ES⁺ m/e 414 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- quinolin-7-yloxy]ethyl}-amine146 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/e 426 (M + 1)b]pyrazol-3-yl)-7-(2-pyrrolidin-1-yl-ethoxy)- quinoline 1477-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-4-(2- MS ES⁺ m/e 455 (M + 1)pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-3-yl)-quinoline 148Dimethyl-{3-[1-oxy-4-(2-pyridin-2-yl-5,6- MS ES⁺ m/e 430 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- quinolin-7-yloxy]-propyl}-amine149 7-Methylsulfanyl-4-(2-pyridin-2-yl-5,6- MS ES⁺ m/e 359.1dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- (M + 1) quinoline 1507-Ethylsulfanyl-4-(2-pyridin-2-yl-5,6- MS ES⁺ m/e 373.2dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- (M + 1) quinoline 1516-Methylsulfanyl-4-(2-pyridin-2-yl-5,6- MS ES⁺ m/e 359.1 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- quinoline 1527-Benzylsulfanyl-4-(2-pyridin-2-yl-5,6- MS ES⁺ m/e 435.4 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- quinoline 1533-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- MS ES⁺ m/e 403.1 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7- ylsulfanyl]-propan-1-ol 154Dimethyl-{2-[4-(2-pyridin-2-yl-5,6-dihydro- MS ES⁺ m/e 416.2 (M + 1)4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7- ylsulfanyl]-ethyl}-amine 155Dimethyl[6-(3-quinolin-4-yl-5,6-dihydro-4H- MS ES⁺ m/e 370 (M + 1)pyrrolo[1,2-b]pyrazol-2-yl)-pyridin-2-yl- methyl]amine 1567-(2-Propoxy-ethoxy)-4-(2-pyridin-2-yl-5,6- MS ES⁺ m/e 415 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- quinoline 157N,N-Dimethyl-N′-[4-(2-pyridin-2-yl-5,6- MS APC⁺ m/e 349 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- pyridin-2-yl]-ethane-1,2-diamine158 N,N-Dimethyl-N′-[4-(2-pyridin-2-yl-5,6- MS CI⁺ m/e 363 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-pyridin-2-yl]-propane-1,3-diamine 1593-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- MS APC⁺ m/e 456 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7- yloxy]-propyl}-oxazolidin-2-one160 1-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- MS APC⁺ m/e 455 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-imidazolidin-2-one 1613-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- MS APC⁺ m/e 504 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-3H-benzooxazol-2-one 162Dimethyl-(2-{4-[2-(6-methyl-pyridin-2-yl)- MS APCI⁺ m/e 3665,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- (M + 1).pyridin-2-ylsulfanyl}-ethyl-amine 163 4-(2-Pyridin-2-yl-5,6-dihydro-4Hpyrrolo[1,2- MS APCI⁺ m/e 382 (M + 1)b]pyrazol-3-yl)-2pyrrolidin-1-yl-quinoline 1642-Phenylsulfanyl-4-(2-pyridin-2-yl-5,6- MS APCI⁺ m/e 421 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- quinoline 1652-Morpholin-4-yl-4-(2-pyridin-2-yl-5,6- MS APCI⁺ m/e 398 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- quinoline 1662-Ethylsulfanyl-4-(2-pyridin-2-yl-5,6- MS APCI⁺ m/e 373 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- quinoline 167Phenyl-[4-(2-pyridin-2-yl-5,6-dihydro-4H- MS APCI⁺ m/e 404 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-2-yl]- amine 1682-Methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H- MS APCI⁺ m/e 344 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 1692-Ethoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H- MS APCI⁺ m/e 357 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 1704-[2-(6-Phenylsulfanyl-pyridin-2-yl)-5,6- MS APCI⁺ m/e APCI⁺ m/edihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- 421 (M + 1) quinoline 171Phenyl-[6-(3-quinolin-4-yl-5,6-dihydro-4H- MS CI⁺ m/e 404 (M + 1)pyrrolo[1,2-b]pyrazol-2-yl)-pyridin-2-yl]- amine 1724-{2-[6-(4-Methoxy-phenyl)-pyridin-2-yl]- MS APCI⁺ m/e 419 (M + 1)5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl}- quinoline 1734-[2-(6-Phenyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI⁺ m/e 389 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl]-quinoline 1744-[2-(6-Morpholin-4-yl-pyridin-2-yl)-5,6- MS APCI⁺ m/e 398 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline 1754-[2-(6-Pyrrolidin-1-yl-pyridin-2-yl)-5,6- MS APCI⁺ m/e 382 (M + 1)dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline 1764-[2-(6-Methoxy-pyridin-2-yl)-5,6-dihydro- MS APCI⁺ m/e 343 (M + 1)4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline 1777-Benzyloxy-4-[2-(6-methyl-pyridin-2-yl)- MS CI⁺ m/e 433 (M + 1)5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- quinoline

EXAMPLE 1782-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-isoindole-1,3-dione

4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol(0.100 g, 0.305 mmol), N-(3-bromopropyl)-phthalimide (0.163 g, 0.609mmol, 2.0 equiv) and cesium carbonate (0.248 g, 0.761 mmol, 2.50 equiv)are combined in N,N-dimethylformamide (1.0 mL) and the reaction isheated at 60° C. for 48 hours. The reaction is diluted with water (1 mL)and the reaction mixture is partitioned between ethyl acetate (6 mL) andwater (5 mL). The organic layer is removed and placed on a 10 g SCXresin column. The resin is washed sequentially with dichloromethane (20mL) and 4:1 dichloromethane/2 N ammonia in methanol (125 mL). The latterfractions are evaporated to dryness and the residue is subjected tochromatography on silica gel (20 g) (9:1 ethyl acetate: methanol (2 Nammonia)) to yield the desired product as a tan solid, 0.117 g (75%).

MS ES⁺ m/e 516 (M+1).

By the above method the following compounds are prepared (unlessotherwise specified:

Product EXAMPLE # (Chemical Name) Physical Data 1797-(3-Fluoro-propoxy)-4-(2-pyridin-2-yl-5,6- MS ES⁺ m/edihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 389 (M + 1) 1807-(3-Chloro-propoxy)-4-(2-pyridin-2-yl-5,6- TOF MS ES⁺ exactdihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline mass calculated forC₂₃H₂₂ClN₄O (p + 1): m/z = 405.1482. Found: 405.1483. 1817-(3-Chloro-propoxy)-6-methoxy-4-(2-pyridin-2- TOF MS ES⁺ exactyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- mass calculated forquinoline C₂₄H₂₄ClN₄O₂ (p + 1): m/z = 435.1588. Found: 435.1595. 1827-(3-Chloro-propoxy)-4-[2-(6-methyl-pyridin-2- MS ES⁺ m/e 419yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- (M + 1) quinoline 183(1-{3-[7-(2-Chloro-ethoxy)-quinolin-4-yl]-5,6- TOF MS ES⁺ exactdihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl}- mass calculated forpropenyl)-methylene-amine C₂₂H₂₀CIN₄O (p + 1): m/z = 391.1325. Found:391.1339. 184 N,N-Diethyl-2-[4-(2-pyridin-2-yl-5,6-dihydro-4H- TOF MSES⁺ exact pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]- mass calculatedfor acetamide C₂₆H₂₈N₅O₂ (p + 1): m/z = 442.2243. Found: 442.2251. 1857-[2-((2R)-1-Methyl-pyrrolidin-2-yl)-ethoxy]-4-(2- MS APC⁺ m/e 440pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- (M + 1)b]pyrazol-3-yl)-quinoline 186Dimethyl-{4-[4-(2-pyridin-2-yl-5,6-dihydro-4H- MS CI⁺ m/e 378pyrrolo[1,2-b]pyrazol-3-yl)-pyridin-2-yloxy]- (M + 1) butyl}-amine 1871-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- MS APC⁺ m/e 404pyrrolo[1,2-b]pyrazol-3-yl)-pyridin-2-yloxy]- (M + 1)propyl}-pyrrolidin-2-one 188 7-(1-Methyl-piperidin-3-ylmethoxy)-4-(2- MSCI⁺ m/e 440 pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- (M + 1)b]pyrazol-3-yl)-quinoline 1897-(3-N,N-Dimethylamino-2-methyl-propyloxy)-4- MS APC⁺ m/e 428(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- (M + 1)b]pyrazol-3-yl)-quinoline 1904-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI⁺ m/e 385pyrrolo[1,2-b]pyrazol-3-yl]-7-propoxy-quinoline (M + 1) 1914-[6-Benzyloxymethyl-2-(6-methyl-pyridin-2- MS CI+ m/e 447yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- (M + 1). quinoline 192{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI+ m/e 415pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yloxy}- (M + 1). acetic acidmethyl ester 193 7-Isopropoxy-4-[2-(6-methyl-pyridin-2-yl)-5,6- MS APCI+m/e 385 dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline (M + 1) 1944-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI+ m/e 470pyrrolo[1,2-b]pyrazol-3-yl)-7-(3-morpholin-4- (M + 1)yl-propoxy)-quinoline 1954-(6-Benzyloxymethyl-2-pyridin-2-yl-5,6-dihydro- MS ES⁺ m/e 433.74H-pyrrolo[1,2-b]pyrazol-6-yl)-quinoline (M + 1) 1967-Benzyloxy-2-Pyridin-2-yl-3-quinolin-4-yl- TOF MS ES⁺ exactpyrazolo[1,5-a]piperidine mass calculated for C₂₈H₂₅N₄O (p + 1): m/z =433.2028 Found: 433.2008 1972-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- TOF MS ES⁺ exactb]pyrazol-3-yl)-quinolin-7-yloxy]-acetamide mass calculated forC₂₂H₂₀N₅O₂ (p + 1): m/z = 444.2399 Found: 444.2391 1987-(5-Phenyl-[1,2,4]oxadiazol-3-ylmethoxy)-4-(2- MS APC⁺ m/e 487pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- (M + 1)b]pyrazol-3-yl)-quinoline 1997-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethoxy)-4- mp: 185-187° C.(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS APC⁺ m/e 410b]pyrazol-3-yl)-quinoline (M + 1) 2007-[2-((2S)-1-Methyl-pyrrolidin-2-yl)-ethoxy]-4-(2- MS APC⁺ m/e 440pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- (M + 1)b]pyrazol-3-yl)-quinoline

EXAMPLE 2015-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxymethyl]-pyrrolidin-2-one

A solution of (R)-(−)-5-(hydroxymethyl)-2-pyrrolidinone (315 mg, 2.74mmol) in N,N-dimethylformamide (3 mL) is treated with methansulfonylchloride (320 mg, 2.74 mmol) and heated at 60° C. for 5 h. The reactionmixture is diluted with N,N-dimethylformamide (1 mL) and4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol(200 mg, 0.91 mmol) added. The mixture is stirred at 60° C. foradditional 16 h, cooled to room temperature, and partitioned betweenethyl acetate and water. The organic portion is washed three times withwater, once with brine, dried (sodium sulfate), filtered andconcentrated in vacuo. The crude residue is chromatographed on SiO₂ (89%dichloromethane 10% methanol 1% concentrated ammonium hydroxide) toyield the title compound, 32 mg (8%), as a light red solid.

MS ES⁺ m/e 426 (M+1).

By the above method the following compounds are prepared (unlessotherwise specified):

Product EXAMPLE # (Chemical Name) Physical Data 2024-(6-Phenoxymethyl-2-pyridin-2-yl-5,6-dihydro- MS CI⁺ m/e4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 419 (M + 1) 2034-(6-Methylene-2-pyridin-2-yl-5,6-dihydro- MS CI+ m/e4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 325 (M + 1) 2043-(4-Fluoro-phenyl)-6-methylene-2-(6-methyl-pyridin-2- MS APCI⁺ m/eyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 306 (M + 1) 2057-(1-Methyl-piperidin-2-ylmethoxy)-4-(2-pyridin-2-yl- MS ES⁺ m/e5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- 441 (M + 1) quinolinehydrochloride 2067-[2-(1-Methyl-pyrrolidin-2-yl)-ethoxy]-4-(2-pyridin-2- MS ES⁺ m/eyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 441 (M + 1)hydrochloride

EXAMPLE 2074-[2-(6-Methyl-1-oxy-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline1-oxide

To a solution of4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline(133 mg, 0.41 mmol) in dichloromethane is added m-chloroperoxybenzoicacid (248 mg, 1.44 mmol) and the resulting mixture stirred for 3 h. Themixture is diluted with dichloromethane and washed twice with saturatedaqueous sodium bicarbonate solution, once with brine, dried (sodiumsulfate), filtered and concentrated in vacuo to yield the titlecompound, 140 mg (96%), as white foam.

TOF MS ES⁺ exact mass calculated for C₂₁H₁₉N₄O₂ (p+1): m/z=359.1508.Found: 359.1516.

By the above method the following compounds are essentially prepared:(unless otherwise specified)

Product EXAMPLE # (Chemical Name) Physical Data 2084-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- TOF MS ES⁺ exact masspyrrolo[1,2-b]pyrazol-3-yl]-quinoline 1-oxide calculated for C₂₁H₁₉N₄O(p + 1): m/z = 343.1559 Found: 343.1566 2094-[2-(6-Methyl-1-oxy-pyridin-2-yl)-5,6- TOF MS ES⁺ exact massdihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- calculated for C₂₁H₁₉N₄Oquinoline (p + 1): m/z = 343.1559 Found: 343.1564 2107-(3-Chloro-propoxy)-4-(2-pyridin-2-yl-5,6- MS ES⁺ m/edihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- 421 (M + 1) quinoline 1-oxide211 7-Methanesulfonyl-4-(2-pyridin-2-yl-5,6- MS ES⁺ m/edihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- 391.1 (M + 1) quinoline 2123-(4-Fluoro-phenyl)-2-(6-methyl-1-oxy- MS ES⁺ m/epyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- 310 (M + 1) b]pyrazole 2134-(Quinolin-N-1-oxide-4-yl)-3-(6- mp: 235-238° C.;methylpyridin-2-yl)-5,6-dihydro-4H- MS ES⁺ m/e pyrrolo[1,2-b]pyrazole377 (M + 1) 214 6-Methanesulfonyl-4-(2-pyridin-2-yl-5,6- MS ES⁺ m/edihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- 391.1 (M + 1) quinoline 2157-Ethanesulfonyl-4-(2-pyridin-2-yl-5,6- MS ES⁺ m/edihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- 405.4 (M + 1) quinoline 2164-(2-Pyridin-2-yl-5,6-dihydro-4H- MS ES⁺ m/epyrrolo[1,2-b]pyrazol-3-yl)-7-[3- 514 (M + 1)(pyrimidine-2-sulfonyl)-propoxy]-quinoline 2177-[3-(1-Methyl-1H-imidazole-2-sulfonyl)- MS ES⁺ m/epropoxy]-4-(2-pyridin-2-yl-5,6-dihydro-4H- 516 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 2187-[3-(4-Chloro-benzenesulfonyl)-propoxy]-4- MS ES⁺ m/e(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- 546 (M + 1)b]pyrazol-3-yl)-quinoline 2194-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-7-[3-(pyridin-2- 527 (M + 1)ylmethanesulfonyl)-propoxy]-quinoline 2204-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-7-[3-(pyridin-2- 511 (M + 1)ylmethanesulfinyl)-propoxy]-quinoline 2214-(Quinolin-1-N-oxide-4-yl)-3-(6- mp: 240-242° C.;methylpyridin-2-yl-1-N-oxide)-5,6-dihydro- MS ES⁺ m/e4H-pyrrolo[1,2-b]pyrazole 393 (M + 1) 2224-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/e 329 (M + 1)b]pyrazol-3-yl)-quinoline 1-oxide

EXAMPLE 2233-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-acrylicacid methyl ester

Nitrogen is bubbled through a solution of7-bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline(0.050 g, 0.12 mmol), tributylamine (0.032 mL, 0.17 mmol), methylacrylate (0.027 mL, 0.24 mmol), and N,N-dimethylformamide (0.5 mL) intoluene (1.0 mL) for 20 min. Pd(OAc)₂ (0.002 g, 0.006 mmol) andtri(o-tolyl)phosphine (0.007 g, 0.021 mmol) are added and nitrogenbubbled through the reaction mixture for 10 min. The mixture is heatedto 80° C. for 24 h. An additional portion of Pd(OAc)₂ (0.002 g, 0.006mmol) and tri(o-tolyl)phosphine (0.007 g, 0.021 mmol) is added andheating continues for another 24 h. The reaction is cooled andconcentrated in vacuo and the residue chromatographed on SiO₂ (2%methanol in methylene choloride) to yield the title compound, 0.49 g(97%), as a yellowish solid.

MS APCI+ m/e 411 (M+1).

By the above method the following compounds are prepared (unlessotherwise specified):

Product EXAMPLE # (Chemical Name) Physical Data 2243-{4-[2-(6-Methylpyrdin-2-yl-5,6-dihydro-4H- MS ES⁺ m/e 464pyrrolo[1,2-b]pyrazol-3-yl]quinolin-7-yl}-1- (M + 1)piperidin-1-yl-propenone 2253-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI+ m/epyrrolo[1,2-b]pyrazol-3-yl]-quinolin-6-yl}-acrylic 411 (M + 1) acidmethyl ester 226 N,N-Dimethyl-3-{4-[2-(6-methyl-pyridin-2-yl)-5,6- MSES⁺ m/e dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7- 424 (M + 1)yl}-acrylamide

EXAMPLE 2274-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-7-vinyl-quinoline

Nitrogen is bubbled through a solution of7-bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline(0.050 g, 0.14 mmol) and tributylvinyltin (0.079 mL, 0.22 mmol) intoluene (2.0 mL) for 20 min. Pd(PPh₃)₂Cl₂ is added and nitrogen bubbledthrough the reaction mixture for another 10 min. The mixture is heatedto 90° C. for 24 h, concentrated in vacuo, and the residuechromatographed on SiO₂ (elute with 2% methanol in methylene choloride)to yield the title compound, 0.030 g (61%), as a yellowish solid.

MS APCI⁺ m/e 353 (M+1).

EXAMPLE 2284-[2-(6-Benzyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline

Zinc(II) chloride (0.34 mL, 1.0 M solution, 0.34 mmol) is added, at roomtemperature with stirring, to a solution of benzyl magnesium chloride(0.15 mL, 2.0 M solution, 0.31 mmol) in tetrahydrofuran (1 mL). After 15min, Pd(PPh₃)₂Cl₂ (5.4 mg, 0.0076 mmol) is added followed by a solutionof4-[2-(6-bromo-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline(60 mg 0.153 mmol) in tetrahydrofuran (1 mL). The reaction mixture isstirred for 18 h at room temperature and quenched with saturated aqueousammonium chloride (1 mL). The reaction mixture is concentrated in vacuo,filtered, and the residue chromatographed on SiO₂ (20-50%acetone/hexanes) to yield the title compound, 33.4 mg (54%), as a whitesolid.

MS (CI, methane) m/e 403 (M+1).

By the above method, the following compounds are essentially prepared.Unless otherwise specified.

Product Physical EXAMPLE # (Chemical Name) Data 2297-Benzyl-4-[2-(6-methyl-pyridin-2-yl)- MS APCI⁺5,6-dihydro-4H-pyrrolo[1,2- m/e 417 b]pyrazol-3-yl]-quinoline (M + 1).

EXAMPLE 2304-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylicacid

To a solution of4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylicacid ethyl ester (250 mg, 0.6 mmol) in methanol (4 mL) at roomtemperature is added 1 N lithium hydroxide (1.2 mL, 1.2 mmol). Themixture is heated at 60° C. for 4 h. The mixture is cooled to roomtemperature and concentrated in vacuo. The mixture is diluted with waterand acidified to pH 6 with 1 N hydrochloric acid. The aqueous solutionis extracted with dichloromethane 5 times. The combined organic extractsare dried (sodium sulfate), filtered, and concentrated in vacuo to yieldthe title compound, 150 mg (65%), as an off white solid.

MS ES⁻ m/e 369 (M−1).

By the above method the following compounds are prepared (unlessotherwise specified):

Product EXAMPLE # (Chemical Name) Physical Data 2314-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI+ m/e 371pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-6- (M + 1) carboxylic acid 2323-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro MS APCI⁺ m/e 3974H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}- (M + 1) acrylic acid 2333-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro- MS APCI+ m/e 3994H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}- (M + 1) propionic acid234 4-[2-(6-Methyl-pyridin-2-yl)-3-quinolin-4-yl-5,6-dihydro- MS APCI+m/e 447 4H-pyrrolo[1,2-b]pyrazol-5-yl]- (M + 1) benzoic acid

EXAMPLE 2354-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylicacid cyclopentylamide

A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride, (53 mg, 0.30 mmol), HOBT, (24 mg, 0.28 mmol),cyclopentylamine (0.03 mL, 0.30 mmol), and4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylicacid (90 mg, 0.25 mmol) in dichloromethane (1 mL) is stirred roomtemperature for 18 h. The mixture is concentrated in vacuo and theresidue chromatographed on SiO₂ to yield the title compound, 31 mg(31%,) as a white solid.

MS APC⁺ m/e 424 (M+1).

By the above method the following compounds are prepared (unlessotherwise specified):

Product EXAMPLE # (Chemical Name) Physical Data 2364-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS ES⁺ m/e3-yl)-quinoline-7-carboxylic acid(2-morpholin-4-yl- 469 (M + 1)ethyl)-amide 237 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-MS ES⁺ m/e 3-yl)-quinoline-7-carboxylic acid[2-(1H 450 (M + 1)-imidazol-4-yl)-ethyl]-amide 2384-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS ES⁺ m/e3-yl)-quinoline-7-carboxylic acid(2-methylamino- 413 (M + 1)ethyl)-amide 239 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-MS ES⁺ m/e 3-yl)-quinoline-7-carboxylic acid(3-methylamino- 427 (M + 1)propyl)-amide 2404-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS ES⁺ m/e3-yl)-quinoline-7-carboxylic acid(2-dimethylamino- 427 (M + 1)ethyl)-amide 241 (4-Methyl-piperazin-1-yl)-[4-(2-pyridin-2-yl-5,6- MSES⁺ m/e dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]- 439(M + 1) methanone 2424-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS APC⁺ m/e3-yl)-quinoline-7-carboxylic acid cyclobutylamide 410 (M + 1) 2434-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS APC⁺ m/e3-yl)-quinoline-7-carboxylic acid cyclopropylamide 396 (M + 1) 2444-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS APC⁺ m/e3-yl)-quinoline-7-carboxylic acid(1-ethyl-propyl)-amide 426 (M + 1) 2454-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS APC⁺ m/e3-yl)-quinoline-7-carboxylic acid ethylamide 384 (M + 1) 2464-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS APC⁺ m/e3-yl)-quinoline-7-carboxylic acid isobutyl-amide 412 (M + 1) 2474-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS APC⁺ m/e3-yl)-quinoline-7-carboxylic acid tert-butylamide 412 (M + 1) 2484-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- mp 240-242° C.3-yl)-quinoline-7-carboxylic acid isopropylamide MS APC⁺ m/e 398 (M + 1)249 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- mp 107-110°C. 3-yl)-quinoline-7-carboxylic acid propylamide MS APC⁺ m/e 398 (M + 1)250 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- mp: 126-128°C. 3-yl)-quinoline-7-carboxylic acid(2-methyl-butyl)-amide MS APC⁺ m/e426 (M + 1) 251 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-mp: 120-122° C. 3-yl)-quinoline-7-carboxylic acid((2S)-2-methyl-butyl)-MS APC⁺ m/e amide 426 (M + 1) 2524-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- mp: 229-231° C.3-yl)-quinoline-7-carboxylic acid(2S)-sec-butylamide MS APC⁺ m/e 412(M + 1) 253 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- mp:229-231° C. 3-yl)-quinoline-7-carboxylic acid(2R)-sec-butylamide MS APC⁺m/e 412 (M + 1) 2544-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- mp: 115-117 ° C.3-yl)-quinoline-7-carboxylic acid((1R)-1,2-dimethyl- MS APC⁺ m/epropyl)-amide 426 (M + 1) 2554-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS APC⁺ m/e3-yl)-quinoline-7-carboxylic acid(pyridin-4-ylmethyl)- 447 (M + 1) amide256 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS APC⁺ m/e3-yl)-quinoline-7-carboxylic acid(pyridin-3-ylmethyl)- 447 (M + 1) amide257 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS APC⁺ m/e3-yl)-quinoline-7-carboxylic acid(pyridin-2-ylmethyl)- 447 (M + 1) amide258 6-(3-Quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-2-yl)-pyridine-2-carboxylic acid amide 356 (M + 1).

EXAMPLE 2591-(4-Methyl-piperazin-1-yl)-2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-ethanone

To a solution of[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-aceticacid (150 mg, 0.39 mmol) in dichloromethane (3 mL) is added oxalylchloride (490 mg, 3.9 mmol) and 1 drop of N,N-dimethylformamide. Themixture is stirred at room temperature for 5 h, concentrated in vacuo,and residual solvents removed by co-evaporation three times withchloroform to yield[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetylchloride as a yellow solid. To a solution of[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetylchloride (50 mg, 0.12 mmol) in dichloromethane at room temperature isadded 1-methyl-piperazine (62 mg, 62 mmol) and the mixture stirred for2.5 h. The mixture is partitioned between dichloromethane and water, theorganic portion dried (sodium sulfate), filtered, and concentrated invacuo. The crude residue is chromatographed on SiO₂ (89% dichloromethane10% methanol 1% concentrated ammonium hydroxide) to yield the titlecompound, 28 mg (48%), as a light brown solid.

MS ES⁺ m/e 469 (M+1).

By the above method the following compounds are essentially prepared:(unless otherwise specified)

Product EXAMPLE # (Chemical Name) Physical Data 260N-(2-Dimethylamino-ethyl)-2-[4-(2-pyridin-2-yl-5,6- MS ES⁺ m/edihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7- 457 (M + 1)yloxy]-acetamide 261N-(2-Dimethylamino-ethyl)-N-methyl-2-[4-(2-pyridin-2- MS ES⁺ m/eyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- 471 (M + 1)3-yl)-quinolin-7-yloxy]-acetamide 262N,N-Dimethyl-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H- MS ES⁺ m/epyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-benzamide 475.8 (M + 1)263 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS ES⁺ m/e3-yl)-quinoline-7-carboxylic acid amide 356 (M + 1) 2644-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-H]pyrazol- MS ES⁺ m/e3-yl)-quinoline-7-carboxylic acid(2-dimethylamino-ethyl)- 441 (M + 1)methyl-amide 265 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-H]pyrazol-LCMS ES⁺ 3-yl)-quinoline-7-carboxylic acid(3-dimethylamino- m/e 454 (M⁺)propyl)-methyl-amide 2664-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-H]pyrazol- LCMS ES⁺3-yl)-quinoline-7-carboxylic acid dimethylamide m/e 383 (M⁺) 2674-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-H]pyrazol- MS ES⁺ m/e3-yl)-quinoline-7-carboxylic acid methylamide 370 (M + 1) 2684-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- LCMS ES⁺3-yl)-quinoline-7-carboxylic acid pyridin-2-ylamide m/e 433 (M⁺) 269N-(2,2-Dimethylamino-ethyl)-N-methyl-3-{4-[2-(6- MS CI⁺ m/emethyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- 483 (M + 1)b]pyrazol-3-yl]-quinolin-7-yl}-propionamide

EXAMPLE 2704-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-6-carboxylicacid (2-dimethylamino-ethyl)-amide

A solution of4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-6-carboxylicacid methyl ester (0.055 g, 0.14 mmol) in 2-N,N-dimethylaminoethylamine(1.5 mL) is heated at 100° C. for 24 h. The mixture is concentrated invacuo and the residue chromatographed on SiO₂ (100% ethyl acetate) toyield the title compound, 0.045 g (74%), as a yellowish solid.

MS APCI⁺ m/e 441 (M+1).

By the above method the following compounds are essentially prepared:(unless otherwise specified)

Product EXAMPLE # (Chemical Name) Physical Data 2714-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI⁺ m/epyrrolo[1,2-b]pyrazol-3-yl]-quinoline-6-carboxylic 455 (M + 1).acid(3-dimethylamino-propyl)-amide 2724-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI⁺ m/epyrrolo[1,2-b]pyrazol-3-yl]-quinoline-6-carboxylic 483 (M + 1)acid(2-morpholin-4-yl-ethyl)-amide 2731-[2-(Quinolin-4-yl)-1-(6-methyl-pyridin-2-yl)-5,6- mp 148-152° C.;dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl] quinoline-7- MS ES⁺ m/e 441carboxylic acid N,N-dimethylaminoethylamide (M + 1). 2744-[2-(6-Methylpyridin-2-yl)-5,6-dihydro4H- mp: 173-175° C.;pyrrolo[1,2-b]pyrazol-3-yl]quinoline-7-carboxylic MS ES⁺ m/e 481acid(2-piperidin-1-yl-ethyl)amide (M + 1) 275N-(2-Dimethylamino-ethyl)-3-{4-[2-(6-methyl-pyridin- MS APCI⁺ m/e2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- 469 (M + 1)quinolin-7-yl}-propionamide 2764-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI⁺ m/epyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic acid 455 (M + 1)(3-dimethylamino-propyl)-amide 2774-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI⁺ m/epyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic 481 (M + 1)acid(3-pyrrolidin-1-yl-propyl)-amide 2784-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI⁺ m/epyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic acid 497 (M + 1)(3-morpholin-4-yl-propyl)-amide 2793-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS APCI⁺ m/epyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}- 398 (M + 1) propionamide 2804-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-6-carboxylic acid(2- 427.2 (M + 1)dimethylamino-ethyl)-amide 2814-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-6-carboxylic acid(2- 469.3 (M + 1)morpholin-4-yl-ethyl)-amide 2824-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-6-carboxylic acid 357.1 (M + 1) 2834-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-6-carboxylic acid hydrazide 371.1 (M + 1) 2844-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-6-carboxylic acid amide 412.3 (M + 1) 2854-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-6-carboxylic acid(3- 427.3 (M + 1)methylamino-propyl)-amide 2864-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-6-carboxylic acid amide 356.1 (M + 1) 2874-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-6-carboxylic acid(2- 400.2 (M + 1)hydroxy-ethyl)-amide 288 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-MS ES⁺ m/e b]pyrazol-3-yl)-quinoline-7-carboxylic acid hydrazide 370.8(M + 1) 289 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-7-carboxylic acid 372.3 (M + 1) hydroxyamide290 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-7-carboxylic acid(2-amino- 399.0 (M + 1)ethyl)-amide 291 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺m/e b]pyrazol-3-yl)-quinoline-7-carboxylic acid(2- 399.8 (M + 1).hydroxy-ethyl)-amide 292 4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MSES⁺ m/e 370 pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic acid(M + 1) amide 293 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS CI⁺m/e 441 b]pyrazol-3-yl)-quinoline-7-carboxylic acid(3- (M + 1)dimethylamino-propyl)-amide 2944-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS ES⁺ m/e 455pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic acid (M + 1)(2-dimethylamino-ethyl)-methyl-amide

EXAMPLE 2954-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-sulfonicacid amide

Molecular chlorine is bubbled through a solution of7-benzylsulfanyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline(190.2 mg, 0.44 mmol) in water (0.3 mL) and glacial acetic acid (1.8 mL)for 10 min. The resultant solution is divided into six 4 mL vials andeach is concentrated. One vial is treated with 7 M ammonia in methanolfor 10 min. The mixture is concentrated in vacuo and the residuechromatographed on SiO₂ (dichloromethane, 2%, and 5%methanol/dichloromethane) to yield the desired product, (17 mg), ascolorless oil.

MS ES⁺ m/e 392.3 (M+1).

By the above method the following compounds are essentially prepared.Unless otherwise specified.

Product Physical EXAMPLE # (Chemical Name) Data 2964-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-7-sulfonic acid methylamide 406.3 (M + 1) 2974-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-7-sulfonic acid 420.4 (M + 1) dimethylamide298 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-7-sulfonic acid(3- 476.9 (M + 1)dimethylamino-propyl)-amide 2994-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-7-sulfonic acid diethylamide 448.4 (M + 1) 3004-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinoline-7-sulfonic acid(2-piperidin- 503.6 (M + 1)1-yl-ethyl)-amide 301 4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MSES⁺ m/e b]pyrazol-3-yl)-quinoline-7-sulfonic acid(2-hydroxy- 436.4(M + 1) ethyl)-amide

EXAMPLE 3024-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ylamine

A solution of7-bromo-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline(135.0 mg, 0.34 mmol), sodium tert-butoxide (64.0 mg, 0.62 mmol), andbenzophonone imine (91.0 mg, 0.51 mmol) in toluene (3 mL) is degassedwith nitrogen for 20 min. To this solution is addedtri(dibenzyldeneacetone)-dipalladium(0) (1.0 mg, 0.0011 mmol) and2,2′-bis(diphenylphosphine)-1,1′-binaphthyl (1.5 mg, 0.0024 mmol) andthe mixture degassed with nitrogen for another 10 min. The mixture isheated at 80° C. for 24 h, cooled to room temperature, quenched withsaturated ammonium chloride, and extracted with chloroform. The combinedorganic portions are washed with water and brine, dried (sodiumsulfate), and concentrated in vacuo. The residue is dissolved in 1 Mhydrochloric acid (5 mL) and heated at reflux for 2.5 h. The mixture isconcentrated in vacuo and the residue neutralized with saturated sodiumbicarbonate. The resultant mixture is extract with chloroform and theorganic extracts concentrated in vacuo to yield the desired product as ayellow solid, 96.5 mg (85%).

MS ES⁺ m/e 327.9 (M+1).

EXAMPLE 3032-Dimethylamino-N-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-acetamide

A mixture of dimethylamino-acetyl chloride (620.0 mg, 13.33 mmol),4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ylamine(75 mg, 0.23 mmol), and 4-N,N-dimethylaminopyridine (10.2 mg, 0.09 mmol)in dry pyridine (1 mL) is refluxed for 72 h. The mixture is treated withsaturated sodium bicarbonate solution and extracted with ethyl acetate.The organic layer is washed with brine, dried (sodium sulfate),concentrated in vacuo, and the residue chromatographed on SiO₂ ((5% to20% methanol in dichloromethane) to yield a yellow oil, 62.3 mg (67%).

MS ES⁺ m/e 413.1 (M+1).

By the above method the following compounds are prepared (unlessotherwise specified):

Product Physical EXAMPLE # (Chemical Name) Data 3043-Dimethylamino-N-[4-(2-pyridin-2-yl-5,6- MS ES⁺ m/e 427.1dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- (M + 1).quinolin-7-yl]propionamide 305 N-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- MSES⁺ m/e 406.1 pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]- (M + 1)methanesulfonamide 306 N-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- MS ES⁺ m/e370.0 pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]- (M + 1) acetamide 3074-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/e 440.9b]pyrazol-3-yl)-quinoline-7-carboxylic acid(2- (M + 1)acetylamino-ethyl)-amide 308 N-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- TOFMS ES⁺ exact mass pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-calculated for propyl}-methanesulfonamide C₂₄H₂₆N₅O₃S (p + 1): m/z =464.1756. Found: 464.1766 309 1-Methyl-1H-imidazole-4-sulfonic acid{3-[4- TOF MS ES⁺ exact mass (2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-calculated for b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}- C₂₇H₂₈N₇O₃S(p + 1): amide m/z = 530.1974 Found: 530.1992 3104-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H- MS CI⁺ m/e 455 (M + 1)pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7- carboxylicacid(2-dimethylamino-1-methyl- ethyl)-amide

EXAMPLE 3111-(2-Dimethylamino-ethyl)-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-urea

To a mixture of 4-(2-pyridin-2-yl-5,6-dihydro-4Hpyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ylamine (38.1 mg, 0.11 mmol) and4-N,N-dimethylaminopyridine (4.2 mg, 0.034 mmol) in dry pyridine (1 mL)is added 20% phosgene in toluene (80 μL, 0.76 mmol). The resultingmixture is stirred at 50° C. for 18 h, treated withN,N-dimethylethylendiame (0.5 mL), and stirred for 4 h. The mixture isconcentrated in vacuo and the residue partitioned between ethyl acetateand brine. The organic layer is dried sodium sulfate), filtered,concentrated in vacuo, and the residue chromatographed on SiO₂ (10%methanol in dichloromethane to water/methanol/dichloromethane: 0.5:3:7)to yield the desired product 14.2 mg (29%).

MS ES⁺ m/e 442.1 (M+1).

By the above method, the following compounds are essentially prepared(unless otherwise specified:

Product Physical EXAMPLE # (Chemical Name) Data 3121-(3-Dimethylamino-propyl)-3-[4-(2-pyridin-2-yl-5,6- MS ES⁺ m/edihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]- 456.2 (M + 1)urea 313 1-(2-Hydroxy-ethyl)-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H- MS ES⁺m/e pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-urea 415.1 (M + 1) 314[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS ES⁺ m/e3-yl)-quinolin-7-yl]-carbamic acid methyl ester 386.0 (M + 1) 315[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS ES⁺ m/e3-yl)-quinolin-7-yl]-carbamic acid 2-hydroxy-ethyl ester 416.4 (M + 1)316 [4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- MS ES⁺ m/e3-yl)-quinolin-7-yl]-carbamic acid 2-methoxy-ethyl ester 430.4 (M + 1)317 1,3-Bis-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- MS ES⁺ m/eb]pyrazol-3-yl)-quinolin-7-yl]-urea 681.1 (M + 1) 318 Dimethyl-carbamicacid 4-(2-pyridin-2-yl-5,6-dihydro-4H- MS ES⁺ m/epyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl ester 399.9 (M + 1)

EXAMPLE 3197-Bromo-2-isopropyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline

A 2 M solution of isopropyl magnesium chloride in tetrahydrofuran (65μL, 0.13 mmol) is added to solution of7-bromo-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline(50.0 mg, 0.13 mmol) in tetrahydrofuran (1 mL) at room, temperature withstirring for 2 h. The mixture is cooled to −78° C. and triethylamine(21.4 μL, 0.154 mmol) and methanesulfonyl chloride (11 μL, 0.14 mmol)added. The mixture is warmed to room temperature and allowed to stand 18h. The mixture is treated with water, extracted with ethyl acetate,dried (sodium sulfate), filtered, and concentrated in vacuo. The residueis chromatographed on SiO₂ (dichloromethane to 75% ethylacetate/dichloromethane) to yield the title compound as a solid, 4.5 mg(9%).

MS ES⁺ m/e 433.1 & 435.1 (M+1).

EXAMPLE 3202-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-6-yl}-propan-2-ol

A solution of4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-6-carboxylicacid methyl ester (0.06 g, 0.16 mmol) in tetrahydrofuran (1 mL) iscooled to −78° C. and degassed with nitrogen for 20 min. To thissolution is added 3 M methylmagnesium chloride in tetrahydrofuran (0.17mmol, 0.06 mL) and the resulting mixture stirred at 0° C. for 2 h. Themixture is treated with aqueous saturated ammonium chloride andextracted with ethyl acetate. The combined organic extracts are washedwith brine, dried (anhydrous sodium sulfate), filtered, andconcentrated, in vacuo. The residue is chromatographed on SiO₂ (100%ethyl acetate) to yield the title compound, 17 mg (28%), as an off-whitefoam.

MS APCI⁺ m/e 385 (M+1).

EXAMPLE 3217-(3-Chloro-propylsulfanyl)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline

To a solution of Preparation #21,3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ylsulfanyl]-propan-1-ol(25.0 mg, 0.062 mmol) in dry pyridine (0.1 mL) is added toluene sulfonylchloride (60.0 mg, 0.31 mmol) and the resulting mixture stirred at roomtemperature for 72 h. Saturated sodium bicarbonate solution is added andthe resulting solution extracted with ethyl acetate. The organic layeris washed with brine, dried (sodium sulfate), filtered, and concentratedin vacuo. Purification of the residue on SiO₂ (5% to 10% methanol indichloromethane) gives the desired product, 11.2 mg (43%). MS ES⁺ m/e421.1 (M+1).

EXAMPLE 3227-Bromo-4-(4-chloro-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline

A solution of 1 M sulfuryl chloride in dichloromethane (20 mL, 20 mmol)is added to a solution of7-bromo-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline(2.2 g, 5.62 mmol) in dry pyridine (50 mL). The mixture is stirred for18 h and concentrated in vacuo. The residue is partitioned betweenchloroform and saturated sodium chloride. The organic layer is dried(sodium sulfate), filtered, concentrated in vacuo, and the residuechromatographed on SiO₂ (dichloromethane to 20% methanol indichloromethane) to yield the title compound as a red solid, 1.8 g(75%).

MS ES⁺ m/e 424.7 & 426.7 (M+1).

By the above method the following compounds are essentially prepared.Unless otherwise specified.

EXAMPLE Product Physical # (Chemical Name) Data 3238-Chloro-4-(2-pyridin-2-yl-5,6-dihydro- MS ES⁺ m/e4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin- 7-ol 363.2 (M + 1) 3248-Bromo-4-(2-pyridin-2-yl-5,6-dihydro- MS ES⁺ m/e4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin- 406.8 & 408.8 7-ol (M + 1)

EXAMPLE 3253-(7-Bromo-quinolin-4-yl)-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-ol

A solution of7-bromo-4-(4-chloro-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline(765.0 mg, 1.80 mmol) in 15% (v/v) aqueous N-methyl pyrrolidinone (15mL) is heated at 120° C. for 18 h. The mixture is concentrated in vacuoand the residue chromatographed on SiO₂ (dichloromethane to 20% methanolin dichloromethane) to yield a yellow solid, 408.0 mg (60%).

MS ES⁺ m/e 406.8 and 408.8 (M+1).

By the above method the following compounds are prepared (unlessotherwise specified):

EXAMPLE Product Physical # (Chemical Name) Data 3267-Bromo-4-(4-methoxy-2-pyridin-2-yl- MS ES⁺ m/e5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- 421.0 & 423.0 3-yl)-quinoline(M + 1) 327 [3-(7-Bromo-quinolin-4-yl)-2-pyridin-2-yl- MS ES⁺ m/e5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4- 420.0 & 422.0 yl]-methyl-amine(M + 1)

EXAMPLE 3283-(7-Bromo-quinolin-4-yl)-2-pyridin-2-yl-5,6-dihydro-pyrrolo[1,2-b]pyrazol-4-one

To a solution of3-(7-bromo-quinolin-4-yl)-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-ol(89.0 mg, 0.22 mmol) in dry dichloromethane (2 mL) is added Dess-Martinperiodinane (301.0 mg, 0.71 mmol) and the resulting mixture stirred for18 h. The reaction mixture is chromatographed on SiO₂ (dichloromethaneto 20% methanol in dichloromethane) to yield a yellow solid, 78 mg(88%).

MS ES⁺ m/e 404.7 and 406.7 (M+1).

EXAMPLE 3293-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-benzonitrile

and3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-benzamide

A mixture of4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol(1.42 g, 4.30 mmol), 3-fluorobenzontrile (550.0 mg, 4.5 mmol),18-crown-6 (80.0 mg, 0.37 mmol), and 37% (w/w) potassium fluoride onalumina (3.5 g) in dimethyl sulfoxide (12 mL) are heated at 140° C. for18 h. The reaction mixture is cooled to room temperature, filtered, andthe solids are washed with chloroform. The organic filtrate is washedwith brine, dried (sodium sulfate), filtered, and concentrated in vacuo.The residue is chromatographed on SiO₂ (dichloromethane to 20% methanolin dichloromethane) to yield a yellow oil.

3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-benzonitrile;

MS ES⁺ m/e 430.1 (M+1).

3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-benzamide;

MS ES⁺ m/e 447.8 (M+1).

By the above method the following compounds are prepared (unlessotherwise specified:

EXAMPLE Product Physical # (Chemical Name) Data 3307-(6-Methyl-pyridazin-3-yloxy)-4- ESMS: 420.2(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1, 2-b]pyrazol-3-yl)-quinoline331 4-(2-Pyridin-2-yl-5,6-dihydro-4H- ESMS: 546.3pyrrolo[1,2-b]pyrazol-3-yl)-7-[4-(4-pyrimidin-2-yl-piperazin-1-yl)-butoxy]- quinoline 3327-{3-[4-(2-Methoxy-phenyl)-piperazin-1- ESMS: 560.3yl]-propoxy}-4-(2-pyridin-2-yl-5,6- dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 333 Pyridin-2-yl-{3-[4-(2-pyridin-2-yl-5,6- ESMS: 462.2dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)- quinolin-7-yloxy]-propyl}-amine

EXAMPLE 334N,N-Dimethyl-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-thiobenzamide

Lawasson's Reagent (1.01 g, 2.49 mmol) is added to a solution ofN,N-dimethyl-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-benzamide(0.72 g, 1.51 mmol) in toluene (10 mL). The resulting mixture is heatedat 120° C. for 45 min. The mixture is concentrated in vacuo and theresidue chromatographed on SiO₂ (dichloromethane to 20% methanol indichloromethane) to yield a red solid, 556 mg (75%).

MS ES⁺ m/e 491.8 (M+1).

EXAMPLE 335Dimethyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-benzyl}-amine

To a refluxing mixture of Raney-nickel and hydrazine-monohydrate (0.5mL, 10.17 mmol) in methanol (5 mL) is addedN,N-dimethyl-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-thiobenzamide(311.0 mg, 0.63 mmol) in methanol (20 mL). The mixture is stirred 10 minand cooled to room temperature, filtered, and concentrated in vacuo. Theresidue is chromatographed by HPLC (C₁₈ column) to yield the titlecompound, 60.2 mg (20%).

MS ES⁺ m/e 462.0 (M+1).

EXAMPLE 3364-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-quinolin-2-one

To a solution of4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-1-oxide(103 mg, 0.30 mmol) in N,N-dimethylformamide (3 mL) is addedtrifluoroacetic anhydride (425 μL, 3.0 mmol). The mixture is stirred for40 h, poured into water, and the pH adjusted to 8 with saturated aqueoussodium bicarbonate solution. The mixture is extracted three times withethyl acetate, the combined organic extracts washed three times withwater and once with brine, dried (sodium sulfate), filtered, andconcentrated in vacuo. The residue is triturated with 10% acetone/90%dichloromethane and filtered. The solid is dried under vacuum to yieldthe title compound, 11.6 mg (10%), as a yellow solid.

TOF MS ES⁺ exact mass calculated for C₂₃H₂₂ClN₄O₂ (p+1): m/z=343.1559.Found: 343.1550.

EXAMPLE 3374-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol

To a solution of7-methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline(53 mg, 0.16 mmol) in N,N-dimethylformamide (3 mL) at room temperatureis added sodium ethanthiolate (133 mg, 1.6 mmol). The solution isrefluxed for 4 h, cooled, and concentrated in vacuo. The residue isdissolved in methanol and loaded onto an SCX column. The column iswashed with water, methanol, and 7 N ammonia in methanol. Theappropriate fraction is concentrated in vacuo to yield the titlecompound, 28 mg (56%), as a yellow solid.

TOF MS ES⁺ exact mass calculated for C₂₀H₁₇N₄O (p+1): m/z=329.1402Found: 329.1413.

By the above method the following compounds are prepared (unlessotherwise specified):

EXAMPLE Product Physical # (Chemical Name) Data 3384-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro- MS APCI+ m/e4H-pyrrolo[1,2-b]Pyrazol-3-yl]-quinolin- 343 (M + 1) 7-ol

EXAMPLE 3396-Methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol:

To a mixture of7-benzyloxy-6-methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline(17 mg, 0.04 mmol) and 10% palladium on activated carbon (3 mg) inabsolute ethanol (2 mL) is added 1,4-cyclohexadiene (100 mg, 1.2 mmol).The mixture is stirred at room temperature for 3 h, treated withmethanol (500 μL), and heated at 60° C. for 3 h. The mixture is cooled,filtered, and loaded onto an SCX column. The column is washed withwater, methanol, and 7 N ammonia in methanol. The appropriate fractionis concentrated in vacuo to yield the title compound, 10 mg (77%), as ayellow solid.

TOF MS ES⁺ exact mass calculated for C₂₁H₁₉N₄O₂ (p+1): m/z=359.1508Found: 359.1520.

EXAMPLE 3403-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-propionicacid methyl ester

To a solution of3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-acrylicacid methyl ester (0.041 g, 0.1 mmol) in methanol (1 mL) is added 10%Pd/C (0.1 g). The resulting mixture is placed under one atmosphere ofhydrogen and: stirred for 18 h. The mixture is filtered and concentratedin vacuo. The residue is chromatographed on SiO₂ (2% methanol indichloromethane) to yield the desired product as a pale yellow solid,0.035 g (85%).

MS APCI⁺ m/e 413 (M+1).

By the above method the following compounds are prepared (unlessotherwise specified):

EXAMPLE Product Physical # (Chemical Name) Data 3414-(6-Methyl-2-pyridin-2-yl-5,6-dihydro- MS APCI⁺ m/e4H-pyrrolo[1,2-b]pyrazol-3-yl)- 327 (M + 1) quinoline 3423-{4-[2-(6-Methyl-pyridin-2-yl)-5,6- MS APCI⁺ m/edihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]- 413 (M + 1)quinolin-6-yl}-propionic acid methyl ester

EXAMPLE 3437-Amino-4-[2-(6-methyl-pyridin-2-3,1)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline

A mixture of7-bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline(1.35 g, 3.34 mmol), sodium t-butoxide (0.64 g, 6.68 mmol), benzophenoneimine (0.91 g, 5.01 mmol) in toluene (30 mL) is de-gassed with nitrogenfor 20 min. To the mixture is added Pd₂(dba)₃ (0.008 g, 0.008 mmol) andBINAP (0.012 g, 0.019 mmol), and further de-gassed with nitrogen for 10min. The mixture is heated at 80° C. for 24 h. Saturated ammoniumchloride (30 mL) is added: and the mixture extracted with chloroform.The combined organic portions are washed with water and brine, dried(sodium sulfate), and concentrated in vacuo. The residue is taken up in1:1 methanol/1 N hydrochloric acid (50 mL) and heated at reflux for 2 h.The mixture is concentrated in vacuo and the residue partitioned betweensaturated sodium bicarbonate and chloroform. The combined organic layersare washed with water and brine, dried (sodium sulfate), filtered, andconcentrated in vacuo. The residue is precipitated from dichloromethanewith hexanes (100 mL) and collected by filtration to yield the titlecompound, 1.10 g (96%), as a yellow solid.

MS APCI⁺ m/e 342 (M+1).

EXAMPLE 344N,N-Dimethyl-3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-propionamide

To a solution of3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-propionicacid methyl ester (0.30 g, 0.73 mmol) and 2M dimethylamine in methanol(1.05 mL, 2.1 mmol) in dichloromethane (1 mL) is added 2 Mtrimethylaluminum in hexane (1.64 mL, 3.25 mmol). The solution is heatedat 40° C. for 48 h. The mixture is diluted with dichloromethane (150mL), treated with saturated potassium sodium tartrate (30 mL), andstirred 18 h. The organic portion is separated and; washed with waterand brine, dried (sodium sulfate), filtered, and concentrated in vacuo.The residue is chromatographed on SiO₂ (10% methanol in dichloromethane)to yield the title compound, 0.29 g (89%), as a yellow foam.

MS APCI⁺ m/e 426 (M+1).

EXAMPLE 345N-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-acetamide

To a solution of3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propylamine(25 mg, 0.06 mmol) in pyridine (1 mL) at room temperature is addedacetic anhydride (500 μL, 5.3 mmol). The mixture is stirred for 2 h,concentrated in vacuo, and the residue chromatographed on SiO₂ (89%dichloromethane 10% methanol 1% concentrated ammonium hydroxide) toyield the title compound, 12 mg (47%), as a light brown solid

TOF MS ES⁺ exact mass calculated for C₂₅H₂₆N₅O₂ (p+1): m/z=428.2086.Found: 428.2095.

By the above method the following compounds are prepared (unlessotherwise specified):

EXAMPLE Product Physical # (Chemical Name) Data 346N-Acetyl-N-{4-[2-(6-methyl-pyridin-2-yl)- MS APCI⁺ m/e5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- 426 (M + 1)yl]-quinolin-7-yl}-acetamide

EXAMPLE 347 2-Pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]piperidin-7-ol

Neat1-(1-aza-2-pyridin-2-yl-3-quinolin-4-yl-prop-1-enyl)piperidine-2,6-dione(0.64 g, 1.8 mmol) is heated at 180° C. for 2 h. After cooling, theresidue is allowed to cool, dissolved in dichloromethane (15 mL), cooledto −70° C., and treated with a 1.0 M solution of DIBAL-H in toluene (1.9mL, 1.9 mmol) dropwise. The mixture is stirred for 0.5 h, the cold bathremoved, and stirred for an additional 18 h. The reaction is dilutedwith saturated aqueous ammonium chloride solution. The mixture ispartitioned between ethyl acetate and water. The organic portion iswashed with water and brine, dried (sodium sulfate), filtered, andconcentrated in vacuo. The residue is precipitated from ethyl acetatewith hexane to yield title compound, 0.58 g (62%), as a white solid.

TOF MS ES+ exact mass calculated for C₂₁H₁₈N₄O (p+1): m/z=343.1559.Found: 343.1570.

EXAMPLE 3487-Acetoxy-2-pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]piperidine

A solution of2-pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]piperidin-7-ol (0.04 g,0.12 mmol) and acetic anhydride (0.2 mL) in pyridine (2 mL) at roomtemperature is stirred for 24 h. The mixture is partitioned betweenethyl acetate and water. The organic portion is washed with water andbrine, dried (sodium sulfate), filtered, and concentrated in vacuo. Theresidue is chromatographed on SiO₂ (5% methanol/dichloromethane) toyield the title compound, 0.41 g (91%), as a white solid.

TOF MS ES+ exact mass calculated for C₂₃H₂₁N₄O₂ (p+1): m/z=385.1665.Found: 385.1668.

EXAMPLE 349Methyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine

A solution ofmethyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-carbamicacid tert-butyl ester (100 mg, 0.2 mmol) in trifluoracetic acid (3 mL)is stirred at room temperature for 6 h. The mixture is concentrated invacuo and traces of trifluoroacetic acid removed by repeated evaporationwith chloroform. The residue is placed on an SCX column and washed withwater, methanol, and 7 N ammonia in methanol. Concentration of theappropriate fraction yields the title compound, 40 mg (50%), as yellowoil.

MS ES⁺ m/e 400 (M+1).

By the above method the following compounds are prepared (unlessotherwise specified):

EXAMPLE Product Physical # (Chemical Name) Data 3507-(Piperidin-4-yloxy)-4-(2-pyridin-2-yl- MS ES+ m/e5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- 412 (M + 1) yl)-quinoline 3514-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro- MS APC⁺ m/e4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline- 469 (M + 1) 7-carboxylic acid(2-amino-1,1-dimethyl- ethyl)-amide

EXAMPLE 352{6-[3-(4-Fluoro-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]-pyridin-2-yl}-methanol

A solution of3-(4-fluoro-phenyl)-2-(6-methyl-1-oxy-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(82 mg, 0.27 mmol) in chloroform (2 mL) is treated with excesstrifluoroacetic anhydride and warmed at reflux for 2 h then concentratedin vacuo. The residue is treated with excess solid potassium carbonatein methanol at reflux for 30 min. The mixture is concentrated, thenpartitioned between ethyl acetate and water. The ethyl acetate portionis concentrated and the residue purified on a silica cartridge (10%pyridine ethyl acetate) to yield 24 mg (29%) of the title compound as ayellow foam.

MS, EI⁺ m/e 310 (M+1).

EXAMPLE 353[6-(3-Quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-pyridin-2-yl]-methanol

To a solution of6-(3-quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)pyridine-2-carboxylicacid methyl ester (0.550 g, 1.48 mmol) in methanol (20 mL) is addedlithium borohydride (35.5 mg, 1.63 mmol). The mixture is stirred 1 h,additional lithium borohydride (35.5 mg, 1.63 mmol) added, and theresulting mixture stirred at room temperature for 16 h. 4 N Hydrochloricacid (3 mL) is added slowly and the resulting mixture concentrated invacuo. The residue is taken up in methanol (10 mL) and partitionedbetween ethyl acetate (150 mL) and saturated potassium carbonate (150mL). The organic portion is washed with brine (150 mL), dried (magnesiumsulfate), and a concentrated in vacuo. The residue is precipitated fromethyl acetate with hexanes to yield 296 mg (58%) of the title compound.

MS ES⁺ m/e 342 (M+1).

EXAMPLE 3544-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-phenol

To a solution of3-(4-methoxy-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(72 mg, 0.24 mmol) in methylene chloride (1 mL) is added borontribromide (0.3 mL). The solution is stirred at ambient temperature for3 h, then quenched with methanol. The mixture is concentrated in vacuoto a reddish solid. The solid is passed through a silica gel cartridge(methylene chloride, ethyl acetate, then acetone). The appropriatemethylene chloride fractions are concentrated in vacuo to yield 4 mg(5.8%) of the title compound. The more polar fractions are concentratedin vacuo then treated with aqueous ammonium chloride and methanol. Themixture is concentrated in vacuo and the residue purified on a silicacartridge eluting as above. Appropriate fractions are combined andconcentrated in vacuo to yield an additional 49 mg (71%) of the titlecompound.

MS ES⁺ m/z 292 (M+1).

EXAMPLE 3557-(1-Methyl-pyrrolidin-3-ylmethoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline

To a 1 M solution of lithium aluminum hydride in tetrahydrofuran (0.60mL, 0.59 mmol) is added a solution of3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxymethyl]-pyrrolidine-1-carboxylicacid benzyl ester (215 mg, 0.39 mmol) in tetrahydrofuran (2 mL). Themixture is heated at 65° C. for 2 h, cooled to 0° C., and diluted withsaturated aqueous sodium potassium tartrate solution. The mixture isextracted with chloroform and the organic portion chromatographed onSiO₂ to yield the title compound, 112 mg (67%), as a yellow foam.

MS APC⁺ m/e 426 (M+1).

By the above method the following compounds are prepared (unlessotherwise specified):

EXAMPLE Product Physical # (Chemical Name) Data 3567-(1-Methyl-piperidin-4-ylmethoxy)-4-(2- MS ES+ m/epyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- 440 (M + 1).b]pyrazol-3-yl)-quinoline

EXAMPLE 3574-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylicacid(2-dimethylamino-1,1-dimethyl-ethyl)-amide

A mixture of4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylicacid(2-amino-1,1-dimethyl-ethyl)-amide (0.12 g, 0.27 mmol), sodiumcyanoborohydride (0.038 g, 0.6 mmol), and acetic acid (0.077 mL, 1.3mmol) in methanol (5 mL) is cooled to 0° C. and stirred for 10 min. Asolution of 37% aqueous formaldehyde (0.086 mL, 3.1 mmol) in methanol (2mL) is added dropwise. The mixture is allowed to warm to roomtemperature and stirred for 1 h. The reaction is quenched with saturatedaqueous potassium carbonate solution and concentrated in vacuo. Theresidue is taken up in chloroform, washed with water and brine, dried(sodium sulfate) and concentrated in vacuo. The residue ischromatographed on SiO₂ (8% methanol/92% dichloromethane) to yield thetitle compound, 33 mg (27%), as a white foam.

MS APC⁺ m/e 469 (M+1).

EXAMPLE 358(S)-[3-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-methanol

To a solution of(S)-6-benzyloxymethyl-3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(0.3 g, 0.73 mmol) in chloroform (1.0 mL) is added trimethylsilyl iodide(0.173 mL, 1.21 mmol). The mixture is stirred 2 h, diluted with methanol(10 mL), stirred 10 min, and concentrated in vacuo. The residue is takenup in ethyl acetate (50 mL), washed with aqueous sodium thiosulfate(2×50 mL), saturated sodium bicarbonate solution, and brine. Theresulting solution is dried (magnesium sulfate), filtered, andconcentrated in vacuo. The residue is chromatographed on SiO₂ (3%methanol/ethyl acetate) to yield the title compound, 149 mg (64%), as apale yellow solid.

MS APCI⁺ m/e 324 (M+1); melting range: 142-144° C.

By the above method the following compounds are essentially prepared.Unless otherwise specified.

EXAMPLE Product Physical # (Chemical Name) Data 359(R)-[3-(4-Fluoro-phenyl)-2-(6-methyl- MS APCI⁺ m/epyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- 324 (M + 1).b]pyrazol-6-yl]-methanol

EXAMPLE 360(S)-[3-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-acetonitrile

A mixture of potassium cyanide (44 mg, 0.67 mmol), tetrabutylammoniumiodide (catalytic), and (S)-methanesulfonic acid3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-ylmethylester (54 mg, 0.135 mmol) in N,N-dimethylformamide (0.35 mL) and water(0.13 mL) is heated at 70° C. for 4 h. The mixture is cooled, taken upin ethyl acetate (20 mL), washed with water and brine, dried (magnesiumsulfate), filtered, and concentrated in vacuo. The residue ischromatographed on SiO₂ (2% methanol/chloroform) to yield the titlecompound, 25 mg (56%).

MS APCI⁺ m/e 333 (M+1).

By the above method the following compounds are prepared (unlessotherwise specified):

EXAMPLE Product Physical # (Chemical Name) Data 361(R)-[3-(4-Fluoro-phenyl)-2-(6-methyl- MS APCI⁺ m/epyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- 333 (M + 1)b]pyrazol-6-yl]-acetonitrile

EXAMPLE 3624-(3-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-quinoline

To a solution of (0.230 g, 1 mmol) of 4-(2-(2-pyridyl)ethynyl)quinolinein xylene (2 mL) is added 3a H-pyrrolidino[1,2-C]1,2,3-oxadiazolin-3-one(0.252 g, 2 mmol) and the resulting solution heated in an oil bath atreflux under argon for 48 h, concentrated in vacuo, and the residuechromatographed on SiO₂ (0 to 1% methanol in chloroform with 3 dropsammonium hydroxide per 150 mL solvent) to yield 18 mg of title compoundas an oil.

MS ES⁺ m/e 313 (M+1).

EXAMPLE 3634-(6-Pyridin-2-yl-2,3-dihydro-pyrazolo[5,1-b]oxazol-7-yl)-quinolinedioxylate salt

To a solution of 5-pyridin-2-yl-4-quinolin-4-yl 2H-pyrazol-3-ol (50 mg,0.17 mmol), ethylene glycol (15 mg, 0.24 mmol) and tri-n-butylphosphine(100 mg, 0.50 mmol) in tetrahydrofuran (15 mL) is added1,1′-(azodicarbonyl)dipiperidine (120 mg, 0.48 mmol). The solution isheated at reflux for 5 h, cooled, and filtered through an SCX cartridge.The residue is chromatographed on SiO₂ (15:1 dichloromethane:methanol).The product residue is converted to the disoxylate salt to give thetitle compound 40 mg (46%).

¹H NMR (CDCl₃): δ 8.81 (d, J=4 Hz, 1H), 8.42 (m, 1H), 8.11 (d, J=8 Hz,1H), 7.83 (d, J=8 Hz, 1H), 7.65 (ddd, J=8, 7, 1 Hz, 1H), 7.46 (ddd, J=8,7, 1 Hz, 1H), 7.38 (ddd, J=8, 7, 1 Hz, 1H) 7.24-7.29 (m, 2H), 7.06-7.10(m, 1H); MS ES⁺ m/e 315.0 (M+1). TOF MS ES⁺ exact mass calculated forC₁₉H₁₅N₄O (p+1): m/z=315.1246. Found: 315.1248.

EXAMPLE 3643-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-oxazolidin-2-one

To a solution of[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-carbamicacid 2-hydroxy-ethyl ester (40.2 mg, 0.097 mmol) and triphenylphosphine(35.0 mg, 0.14 mmol) in tetrahydrofuran (1 mL) at room temperature isadded diethyl 40% azodicarboxylate in toluene (50 μL, 0.11 mmol). Themixture is stirred 18 h, filtered, and the filtrate concentrated invacuo. The residue is chromatographed on SiO₂ (2% to 15% methanol indichloromethane) to yield the desired product, 15.2 mg (40%).

MS ES⁺ m/e 398.0 (M+1).

By the above method the following compound are prepared (unlessotherwise specified):

EXAM- Product Physical PLE # (Chemical Name) Data 3651-[4-(2-Pyridin-2-yl-5,6-dihydro-4H- MS ES⁺ m/epyrrolo[1,2b]pyrazol-3-yl)-quinolin-7-yl]- 397.4 (M + 1)imidazolidin-2-one

EXAMPLE 3664-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-(pyridin-4-ylmethoxy)-quinoline

4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol(0.100 g, 0.305 mmol), triphenylphosphine (0.080 g, 0.305 mmol), and4-pyridylcarbinol (0.033 g, 0.305 mmol) are combined in toluene (1.0 mL)and treated with diisopropylazodicarboxylate (0.062 g, 0.305 mmol). Theresulting mixture is heated at 75° C. for 18 hours. The mixture isdiluted with tetrahydrofuran and heated at 75° C. for 24 h. The mixtureis placed on a 10 g SCX resin column which is washed sequentially withdichloromethane (120 mL), methanol (60 mL), and 4:1 dichloromethane/2 Nammonia in methanol (125 mL). The latter fraction is concentrated invacuo and the residue chromatographed on SiO₂ (9:1 ethyl acetate:2Nammonia in methanol) to yield the desired product as a tan solid, 0.035g (27%).

MS ES⁺ m/e 420 (M+1).

By the above method the following compound is prepared (unless otherwisespecified):

EXAMPLE # Product Name Physical Data 3674-(2-Pyridin-2-yl-5,6-dihydro-4H- MS ES⁺ m/epyrrolo[1,2-b]pyrazol-3-yl)-7-(3-pyridin- 448 (M + 1)3-yl-propoxy)-quinoline

EXAMPLE 3687-(4,5-Dihydro-1H-imidazol-2-yl)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline

Ethylenediame (45 mL, 0.67 mmol) is added dropwise to a stirred solutionof 2.0 M trimethylaluminum in toluene (0.5 mL, 1.0 mmol) and4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-6-carboxylicacid methyl ester (250.0 mg, 0.675 mmol) at 0° C. The mixture is warmedto room temperature, then refluxed for 3 h. The solution is cooled anddiluted with water (0.5 mL) and methanol (1 mL). The mixture is refluxedfor 10 min, cooled, filtered, extracted into chloroform, and the organicportion washed with brine. The organic layer is concentrated in vacuoand the residue is chromatographed on SiO₂ (10% to 30% methanol indichloromethane) to yield the title compound, 46 mg (18%), as an yellowoil.

MS ES⁺ m/e 381.0 (M+1).

EXAMPLE 3694-[5-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline

Racemic4-[5-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline(110 mg, 0.26 mmol) is separated into pure enantiomers by preparativeHPLC with a Chiralcel OD (50×500 mm) column (25:75 isopropanol/heptaneand detector at 220 nm). Fractions containing the first eluting compoundare combined and concentrated to yield the title compound, 44 mg (40%),as an off-white foam.

¹H NMR (CDCl₃): δ 8.85 (d, J=4.5 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.80(d, J=8.4 Hz, 1H), 7.65 (td, J=1.5, 8 Hz, 1H), 7.35 (td, J=1.5, 8 Hz,1H), 7.20-7.30 (m, 4H), 6.85-7.10 (m, 4H), 4.80 (dd, J=8.4, 11 Hz, 1H),4.35 (dd, J=7, 11 Hz, 1H), 4.15-4.25 (m, 1H), 3.30 (dd, J=8.4, 16 Hz,1H), 2.85 (dd, J=6, 16 Hz, 1H), 2.30 (s, 3H). MS APCI⁺ m/e 421 (M+1).

EXAMPLE 3704-[5-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline

Racemic4-[5-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]_(j)-quinoline(110 mg, 0.26 mmol) is separated into pure enantiomers by preparativeHPLC with a Chiralcel OD (50×500 mm) column (25:75 isopropanol/heptaneand detector at 220 nm). Fractions containing the second elutingcompound are combined and concentrated to give the title compound, 59 mg(54%), as an off-white foam.

¹H NMR (CDCl₃): δ 8.85 (d, J=4.5 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.80(d, J=8.4 Hz, 1H), 7.65 (td, J=1.5, 8 Hz, 1H), 7.35 (td, J=1.5, 8 Hz,1H), 7.20-7.30 (m, 4H), 6.85-7.10 (m, 4H), 4.80 (dd, J=8.4, 11 Hz, 1H),4.35 (dd, J=7, 11 Hz, 1H), 4.15-4.25 (m, 1H), 3.30 (dd, J=8.4, 16 Hz,1H), 2.85 (dd, J=6, 16 Hz, 1H), 2.30 (s, 3H). MS APCI⁺ m/e 421 (M+1).

EXAMPLE 3714-[2-(6-Vinyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline

Add tributylvinyltin (0.059 mL, 0.19 mmol) to a solution of4-[2-(6-chloro-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline,EXAMPLE 101, (59 mg, 0.17 mmol) in toluene (0.7 mL) at RT. Bubblenitrogen into the reaction mixture for 5 min and addtetrakis-(triphenylphosphine) palladium (0) (10 mg, 0.0085 mmol). Bubblenitrogen into the solution for an additional 2 min and heat the reactionto 110° C. for 18 h. Concentrate the reaction in vacuo and purify byflash column chromatography (SiO2, 20-40% acetone/hexanes) to providethe title compound (35 mg, 62%) as a white solid.

MS Calcd. 338; MS (APCI) (M+1) 339.

EXAMPLE 3723-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-6-yl}-acrylicacid

Dissolve3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-6-yl}-acrylicacid methyl ester (0.040 g, 0.1 mmol) in methanol/water (3:1, 2 mL). Addlithium hydroxide (0.010 g, 0.25 mmol) and stir the mixture 18 h. Removethe solvent then load the residue on a SCX resin column with methanol.Elute the column with methanol (50 mL) then with 2 N ammonia/methanol togive the desired product as a pale yellow solid 0.036 g (92%)

MS APCI⁺ m/e 397 (M+1).

The compounds disclosed herein were tested by the following protocolsfor TGF-β inhibition, as described below in the protocol description.The data collected thereby is shown below.

TGF-β Receptor I and II Purification and in vitro Kinase Reactions

For TGF-β Type I (RIT204D) and Type II (RII WT) Receptors: The 6×-HIStagged cytoplasmic kinase domain of each receptor was expressed andpurified from Sf9 insect cell lysates as briefly described below:

Cell pellets after 48-72 hrs of infection were lysed in lysis buffer(LB: 50 mM Tris pH 7.5, 150 mM NaCl, 50 mM NaF, 0.5% NP40 with freshlyadded 20 mM, β-mercaptoethanol, 10 mM imidazole, 1 mM PMSF, 1×EDTA-freeComplete Protease Inhibitor (Boehringer Mannheim).

Cell lysates were clarified: by centrifugation and 0.45 uM filteredprior to purification by Ni/NTA affinity chromatography (Qiagen).

Chromatography Protocol:

Equilibrate with 10 CV of LB, load sample, wash with 10 CV RIPA buffer(50 mM Tris pH 7.5, 150 mM NaCl, 1% NP40, 1 mM EDTA, 0.25% sodiumdeoxycholate, added fresh 20 mM β-mercaptoethanol, 1 mM PMSF), wash with10 CV LB, wash with 10 CV 1×KB (50 mM Tris pH 7.5, 150 mM NaCl, 4 mMMgCl₂, 1 mM NaF, 2 mM β-mercaptoethanol), elute with a linear gradientof 1×KB containing 200 mM Imidazole.

Both enzymes were approximately 90% pure and had autophosphorylationactivity.

Reactions: 170-200 nM enzyme in 1×KB, compound dilution series in1×KB/16% DMSO (20 uM to 1 nM final concentration with 4% DMSO finalconcentration), reactions started by adding ATP mix (4 uM ATP/1 uCi³³P-□-ATP final concentrations) in 1×KB.

Reactions were incubated at 30° C. for 1 hr RIT204D or 40 min for RIIWT. Reactions were stopped and quantitated using standard TCA/BSAprecipitation onto Millipore FB glass fiber filter plates and by liquidscintillation counting on a MicroBeta JET.

Representative data for compounds of the current invention with theRIT204D IC50<20.00 (uM) are given in Table I.

TGF-β Receptor I

Table I:

TABLE 1 COMPOUND NAME7-Methanesulfonyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline4-(2-Thiophen-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline4-[2-(6-Benzyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline2-(6-methyl-pyridin-2-yl)-3-pyridin-3-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoleN,N-Dimethyl-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-benzamide4-[2-(3-Chloro-phemyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-alpyridin-3-y]-quinolineN,N-Dimethyl-N′-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-pyridin-2-yl]-propane-1,3-diamineDimethyl-{4-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-pyridin-2-yloxy]-butyl}-amine4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-H]pyrazol-3-yl)-quinoline-7-carboxylicacid(3-dimethylamino-propyl)-methyl-amide4-[2-(3-Trifluoromethoxy-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline3-(4-Fluorophenyl)-2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole3-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-acrylic acid methyl ester3-(4-Methoxyphenyl)-2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-H]pyrazol-3-yl)-quinoline-7-carboxylicacid methylamideN-{3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-acetamide4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylicacid propylamideDimethyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amineN-(2-dimethylamino-ethyl)-2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetamideDimethyl-{2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-ethyl}-amine

Representative data for compounds of the current invention with the RIIWT IC50<20.00 (uM) are given in Table II.

TGF-β Receptor II

Table II:

TABLE II COMPOUND NAMEDimethyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amineN-(2-Dimethylamino-ethyl)-2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetamideDimethyl-{2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-ethyl}-amine7-Bromo-2-isopropyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline4-[2-(3-Trifluoromethylphenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-6-phenyl-quinoline4-(Quinolin-4-yl)-3-(5-fluoropyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylicacid(2-methyl-butyl)-amide4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylicacid pyridin-2-ylamide4-[5-(3-Methoxy-phenyl)-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline.[3-(7-Bromo-quinolin-4-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]3-methanol7-(3-Chloro-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline 2-Pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]piperidin-7-ol4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylicacid cyclopropylamide4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-ylamine3-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-acrylic acid3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-oxazolidin-2-one3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ylsulfanyl]-propan-1-ol4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-H]pyrazol-3-yl)-quinoline-7-carboxylicacid methylamideEthyl-methyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine

MV1LU p3TP-Lux Assay

A stable Mv1Lu clone (C1) containing the p3TP-Lux reporter was createdby standard transfection and puromycin selection protocols. This stableclone was used to screen the example compounds for their ability toinhibit TGF-β dependent luciferase production as briefly describedbelow:

-   -   1. Plated Mv1Lu C1 cells in Wallac™ Black Isoplates    -   2. Allowed cells to adhere overnight.    -   3. Removed media and replaced with 0.5% FBS DMEM media    -   4. Added the compound dilution series in 0.5% FBS/DMEM        containing 1% DMSO such that the final compound concentration        ranged from 20 uM to 0.1 nM and the final DMSO concentration was        0.2%.    -   5. Incubated at 37° C./5% CO₂ for 2 hrs.    -   6. Added 0.5% FBS/DMEM as control or TGF-β1 diluted in 0.5%        FBS/DMEM (final concentration of 10 pM) to the −/+ TGF-β wells        respectively    -   7. Incubated for 16-20 hrs. at 37° C./5% CO₂    -   8. Removed media and rinsed 1× with PBS.    -   9. Removed PBS and lysed the cells with 1× Passive Lysis Buffer        (Promega) at room temperature.    -   10. Counted relative luciferase activity on the MicroBeta JET by        injecting Luciferase Assay Reagent II (PROMEGA).

The use of the above assay in measuring TGF-β responsive activity isdescribed in Wrana, et al. Cell 71: 1003-1014 (1992).

Representative data for compounds of the current invention with thep3TP-LUX IC50<20.00 (uM) are given in Table III.

MV1LU p3TP-Lux/Assay

Table III:

TABLE III COMPOUND NAME4-[5-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline(Enantiomer B)3-(2-Chloro-pyridin-4-yl)-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-6-carboxylicacid hydrazide2-(6-methyl-pyridin-2-yl)-3-naphthalen-1-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole2-{4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-6-yl}-propan-2-ol6-Benzo[1,3]dioxol-5-yl-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline8-Fluoro-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline5-(4-Chloro-phenyl)-3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole4-(6-Hydroxymethyl-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3yl)-quinoline4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-6-carboxylic acid methyl esterN,N-Dimethyl-3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-propionamide4-[2-(6-Methylpyridin-2-yl)-5,6-dihydro4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-7-carbox-ylic acid(2-piperidin-1-yl-ethyl)amide7-(3-chloro-propoxy)-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline7-(3-azepan-1-yl-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline[6-(3-Quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-pyridin-2-yl]-methanol4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-H]pyrazol-3-yl)-quinoline-7-carboxylicacid(2-dimethylamino-ethyl)-methyl-amide

p38α in vitro Kinase Assay

Active p38α/SAPK2α was purchased from Upstate Biotechnology(cat#14-251). A known p38α substrate from EGFR was used in the assay(Young, et al. (1997) JBC 272: 12116-12121).

Reactions were performed in 1× kinase buffer (25 mM Tris-HCl pH 7.5, 5mM β-glycerophosphate, 2 mM DTT, 0.1 mM Na₃VO₄, 10 mM MgCl₂, 1 uMMicrocystin) with 5 nM p38α, 62.5 uM substrate, 40 uM to 0.2 nM compounddilution series in 1×KB/16% DMSO (final 4% DMSO concentration).Reactions were started by addition of 100 uM ATP (final concentration)with 1 uCi ³³P-γ-ATP in 1×KB and incubated at 30° C. for 40 min.Reactions were stopped with H₃PO₄ and quantitated on Millipore PHphosphocellulose filter plates by liquid scintillation counting on aMicroBeta JET.

Representative data for compounds of the current invention with the p38αIC50<20.00 (uM) are given in Table IV.

p38α/SAPK2α

Table IV:

TABLE IV COUMPOUND NAME3-Benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-H]pyrazol-3-yl)-quinoline-7-carboxylic acid methylamide3-Naphthalen-2-yl-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole3-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ylsulfanyl]-propan-1-ol6-(4-Fluoro-phenyl)-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline7-[3-(4-Methyl-piperazin-1-yl)-propoxy]-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline7-Methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline7-(3-Imidazol-1-yl-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline4-[2-(4-Fluoro-phenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline7-Amino-4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline6-Methylsulfanyl-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline4-[2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic acid methyl ester4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic acid [2-(1H-imidazol-4-yl)-ethyl]- amide(R)-[3-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-acetonitrile2-Dimethylamino-N-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-acetamide4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-6-carboxylic acid

KDR (VEGFR2) Purification and in vitro Kinase Assay

The 6×-HIS tagged cytoplasmic kinase domain of KDR was expressed andpurified from Sf9 insect cell lysates as described above with thefollowing modification:

1× kinase buffer for chromatography washes and elution was changed to100 mM HEPES pH 7.5, 10 mM MnCl₂ and 5 mM β-mercaptoethanol. Theresulting material was approximately 40% pure and had tyrosineautophosphorylation activity.

Reactions: 1 ug enzyme in 1×KB, compound dilution series in 1×KB/16%DMSO (20 uM to 1 nM final concentration with 4% DMSO finalconcentration), reactions were started by adding ATP mix (1 uM ATP/1 uCi³³P-□-ATP final concentrations) in 1×KB.

Reactions were incubated at 30° C. for 20 min. The reactions werestopped and quantitated using standard TCA/BSA precipitation ontoMillipore FC glass fiber filter plates and by liquid scintillationcounting on a MicroBeta JET.

Representative data for compounds of the current invention with the KDRIC50<20.00 (uM) are given in Table V.

KDR (VEGFR2)

Table V:

TABLE V COMPOUND NAME4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-(3-[1,2,3]triazol-1-yl-propoxy)-quinolineBenzyl-methyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-amine4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-7-(3-morpholin-4-yl-propoxy)-quinoline4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic acid (3-dimethylamino-propyl)-amide4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-(3-pyrrolidin-1-yl-propoxy)-quinolineN,N-Dimethyl-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-benzamide4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic acid (2-acetylamino-ethyl)-amide4-[2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic acid methyl ester3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propylamine4-(6-Pyridin-2-yl-2,3-dihydro-pyrazolo[5,1-b]oxazol-7-yl)- quinoline(1-{3-[7-(2-Chloro-ethoxy)-quinolin-4-yl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl}-propenyl)-methylene-amine4-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-7-carboxylic acid methyl esterDiethyl-(3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yloxy}-propyl)- amine4-(7-Ethoxyquinolin-4-yl)-3-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Conditions “characterized by enhanced TGF-β activity” include thosewherein TGF-β synthesis is stimulated so that TGF-β is present atincreased levels or wherein TGF-β latent protein is undesirablyactivated or converted to active TGF-β protein or wherein TGF-βreceptors are upregulated or wherein the TGF-β protein shows enhancedbinding to cells or extracellular matrix in the location of the disease.Thus, in either case “enhanced activity” refers to any condition whereinthe biological activity of TGF-β is undesirably high, regardless of thecause.

A number of diseases have been associated with TGF-β1 over production.Inhibitors of TGF-β intracellular signaling pathway are usefultreatments for fibroproliferative diseases. Specifically,fibroproliferative diseases include kidney disorders associated withunregulated TGF-β activity and excessive fibrosis includingglomerulonephritis (GN), such as mesangial proliferative GN, immune GN,and crescentic GN. Other renal conditions include diabetic nephropathy,renal interstitial fibrosis, renal fibrosis in transplant patientsreceiving cyclosporin, and HIV-associated nephropathy. Collagen vasculardisorders include progressive systemic sclerosis, polymyositis,scleroderma, dermatomyositis, eosinophilic fascitis, morphea, or thoseassociated with the occurrence of Raynaud's syndrome. Lung fibrosesresulting from excessive TGF-β activity include adult respiratorydistress syndrome, idiopathic pulmonary fibrosis, and interstitialpulmonary fibrosis often associated with autoimmune disorders, such assystemic lupus erythematosus and scleroderma, chemical contact, orallergies. Another autoimmune disorder associated withfibroproliferative characteristics is rheumatoid arthritis.

Eye diseases associated with a fibroproliferative condition includeretinal reattachment surgery accompanying proliferativevitreoretinopathy, cataract extraction with intraocular lensimplantation, and post glaucoma drainage surgery are associated withTGF-β1 overproduction.

Fibrotic diseases associated with TGF-β1 overproduction can be dividedinto chronic conditions such as fibrosis of the kidney, lung and liverand more acute conditions such as dermal scarring and restenosis(Chamberlain, J. Cardiovascular Drug Reviews, 19(4):329-344). Synthesisand secretion of TGF-β1 by tumor cells can also lead to immunesuppression such as seen in patients with aggressive brain or breasttumors (Arteaga, et al. (1993) J. Clin. Invest. 92:2569-2576). Thecourse of Leishmanial infection in mice is drastically altered by TGF-β1(Barral-Netto, et al. (1992) Science 257:545-547). TGF-β1 exacerbatedthe disease, whereas TGF-β1 antibodies halted the progression of thedisease in genetically susceptible mice. Genetically resistant micebecame susceptible to Leishmanial infection upon administration ofTGF-β1.

The profound effects of TGF-β1 on extracellular matrix deposition havebeen reviewed (Rocco and Ziyadeh (1991) in Contemporary Issues inNephrology v.23, Hormones, autocoids and the kidney. ed. Jay Stein,Churchill Livingston, New York pp.391-410; Roberts, et al. (1988) Rec.Prog. Hormone Res. 44:157-197) and include the stimulation of thesynthesis and the inhibition of degradation of extracellular matrixcomponents. Since the structure and filtration properties of theglomerulus are largely determined by the extracellular matrixcomposition of the mesangium and glomerular membrane, it is notsurprising that TGF-β1 has profound effects on the kidney. Theaccumulation of mesangial matrix in proliferative glomerulonephritis(Border, et al. (1990) Kidney Int. 37:689-695) and diabetic nephropathy(Mauer, et al. (1984) J. Clin. Invest. 74:1143-1155) are clear anddominant pathological features of the diseases. TGF-β1 levels areelevated in human diabetic glomerulosclerosis (advanced neuropathy)(Yamamoto, et al. (1993) Proc. Natl. Acad. Sci. 90:1814-1818). TGF-β1 isan important mediator in the genesis of renal fibrosis in a number ofanimal models (Phan, et al. (1990) Kidney Int. 37:426; Okuda, et al.(1990) J. Clin. Invest. 86:453). Suppression of experimentally inducedglomerulonephritis in rats has been demonstrated by antiserum againstTGF-β1 (Border, et al. (1990) Nature 346:371) and by an extracellularmatrix protein, decorin, which can bind TGF-β1 (Border, et al. (1992)Nature 360:361-363).

Too much TGF-β1 leads to dermal scar-tissue formation. NeutralizingTGF-β1 antibodies injected into the margins of healing wounds in ratshave been shown to inhibit scarring without interfering with the rate ofwound healing or the tensile strength of the wound (Shah, et al. (1992)Lancet 339:213-214). At the same time there was reduced angiogenesis,reduced number of macrophages and monocytes in the wound, and a reducedamount of disorganized collagen fiber deposition in the scar tissue.

TGF-β1 may be a factor in the progressive thickening of the arterialwall which results from the proliferation of smooth muscle cells anddeposition of extracellular matrix in the artery after balloonangioplasty. The diameter of the restenosed artery may be reduced 90% bythis thickening, and since most of the reduction in diameter is due toextracellular matrix rather than smooth muscle cell bodies, it may bepossible to open these vessels to 50% simply by reducing extensiveextracellular matrix deposition. In uninjured pig arteries transfectedin vivo with a TGF-β1 gene, TGF-β1 gene expression was associated withboth extracellular matrix synthesis and hyperplasia (Nabel, et al.(1993) Proc. Natl. Acad. Sci. USA 90:10759-10763). The TGF-β1 inducedhyperplasia was not as extensive as that induced with PDGF-BB, but theextracellular matrix was more extensive with TGF-β1 transfectants. Noextracellular matrix deposition was associated with FGF-1 (a secretedform of FGF) induced hyperplasia in this gene transfer pig model (Nabel(1993) Nature 362:844-846).

There are several types of cancer where TGF-β1 produced by the tumor maybe deleterious. MATLyLu rat prostate cancer cells (Steiner and Barrack(1992) Mol. Endocrinol 6:15-25) and MCF-7 human breast cancer cells(Arteaga, et al. (1993) Cell Growth and Differ. 4:193-201) became moretumorigenic and metastatic after transfection with a vector expressingthe mouse TGF-β1. TGF-β1 has been associated with angiogenesis,metastasis and poor prognosis in human prostate and advanced gastriccancer (Wikstrom, P., et al. (1998) Prostate 37: 19-29; Saito, H. et al.(1999) Cancer 86: 1455-1462). In breast cancer, poor prognosis isassociated with elevated TGF-β (Dickson, et al. (1987) Proc. Natl. Acad.Sci. USA 84:837-841; Kasid, et al. (1987) Cancer Res. 47:5733-5738;Daly, et al. (1990) J. Cell Biochem. 43:199-211; Barrett-Lee, et al.(1990) Br. J. Cancer 61:612-617; King, et al. (1989) J. Steroid Biochem.34:133-138; Welch, et al. (1990) Proc. Natl. Acad. Sci. USA87:7678-7682; Walker, et al. (1992) Eur. J. Cancer 238:641-644) andinduction of TGF-β1 by tamoxifen treatment (Butta, et al. (1992) CancerRes. 52:4261-4264) has been associated with failure of tamoxifentreatment for breast cancer (Thompson, et al. (1991) Br. J. Cancer63:609-614). Anti TGF-β1 antibodies inhibit the growth of MDA-231 humanbreast cancer cells in athymic mice (Arteaga, et al. (1993) J. Clin.Invest. 92:2569-2576), a treatment which is correlated with an increasein spleen natural killer cell activity. CHO cells transfected withlatent TGF-β1 also showed decreased NK activity and increased tumorgrowth in nude mice (Wallick, et al. (1990) J. Exp. Med. 172:1777-1784).Thus, TGF-β secreted by breast tumors may cause an endocrine immunesuppression. High plasma concentrations of TGF-β1 have been shown toindicate poor prognosis for advanced breast cancer patients (Anscher, etal. (1993) N. Engl. J. Med. 328:1592-1598). Patients with highcirculating TGF-β before high dose chemotherapy and autologous bonemarrow transplantation are at high risk for hepatic veno-occlusivedisease (15-50% of all patients with a mortality rate up to 50%) andidiopathic interstitial pneumonitis (40-60% of all patients). Theimplication of these findings is 1) that elevated plasma levels ofTGF-β1 can be used to identify at risk patients and 2) that reduction ofTGF-β1 could decrease the morbidity and mortality of these commontreatments for breast cancer patients.

Many malignant cells secrete transforming growth factor-β (TGF-β), apotent immunosuppressant, suggesting that TGF-β production may representa significant tumor escape mechanism from host immunosurveillance.Establishment of a leukocyte sub-population with disrupted TGF-βsignaling in the tumor-bearing host offers a potential means forimmunotherapy of cancer. A transgenic animal model with disrupted TGF-βsignaling in T cells is capable of eradicating a normally lethal TGF-βoverexpressing lymphoma tumor, EL4 (Gorelik and Flavell, (2001) NatureMedicine 7(10): 1118-1122). Down regulation of TGF-β secretion in tumorcells results in restoration of immunogenicity in the host, while T-cellinsensitivity to TGF-β results in accelerated differentiation andautoimmunity, elements of which may be required in order to combatself-antigen-expressing tumors in a tolerized host. Theimmunosuppressive effects of TGF-β have also been implicated in asubpopulation of HIV patients with lower than predicted immune responsebased on their CD4/CD8 T cell counts (Garba, et al. J. Immunology (2002)168: 2247-2254). A TGF-β neutralizing antibody was capable of reversingthe effect in culture, indicating that TGF-β signaling inhibitors mayhave utility in reversing the immune suppression present in this subsetof HIV patients.

During the earliest stages of carcinogenesis, TGF-β1 can act as a potenttumor suppressor and may mediate the actions of some chemopreventiveagents. However, at some point during the development and progression ofmalignant neoplasms, tumor cells appear to escape from TGF-β-dependentgrowth inhibition in parallel with the appearance of bioactive TGF-β inthe microenvironment. The dual tumor suppression/tumor promotion rolesof TGF-β have been most clearly elucidated in a transgenic systemoverexpressing TGF-β in keratinocytes. While the transgenics were moreresistant to formation of benign skin lesions, the rate of metastaticconversion in the transgenics was dramatically increased (Cui, et al(1996) Cell 86(4):531-42). The production of TGF-β1 by malignant cellsin primary tumors appears to increase with advancing stages of tumorprogression. Studies in many of the major epithelial cancers suggestthat the increased production of TGF-β by human cancers occurs as arelatively late event during tumor progression. Further, thistumor-associated TGF-β provides the tumor cells with a selectiveadvantage and promotes tumor progression. The effects of TGF-β oncell/cell and cell/stroma interactions result in a greater propensityfor invasion and metastasis. Tumor-associated TGF-β may allow tumorcells to escape from immune surveillance since it is a potent inhibitorof the clonal expansion of activated lymphocytes. TGF-β has also beenshown to inhibit the production of angiostatin. Cancer therapeuticmodalities such as radiation therapy and chemotherapy induce theproduction of activated TGF-β in the tumor, thereby selecting outgrowthof malignant cells that are resistant to TGF-β growth inhibitoryeffects. Thus, these anticancer treatments increase the risk and hastenthe development of tumors with enhanced growth and invasiveness. In thissituation, agents targeting TGF-β-mediated signal transduction might bea very effective therapeutic strategy. The resistance of tumor cells toTGF-β has been shown to negate much of the cytotoxic effects ofradiation therapy and chemotherapy and the treatment-dependentactivation of TGF-β in the stroma may even be detrimental as it can makethe microenvironment more conducive to tumor progression and contributesto tissue damage leading to fibrosis. The development of a TGF-β signaltransduction inhibitors is likely to benefit the treatment of progressedcancer alone and in combination with other therapies.

The compounds are useful for the treatment of cancer and other diseasestates influenced by TGF-β by inhibiting TGF-β in a patient in needthereof by administering said compound(s) to said patient. TGF-β wouldalso be useful against atherosclerosis (T. A. McCaffrey: TGF-βs andTGF-β Receptors in Atherosclerosis: Cytokine and Growth Factor Reviews2000, 11, 103-114) and Alzeheimer's (Masliah, E.; Ho, G.; Wyss-Coray,T.: Functional Role of TGF-β in Alzheimer's Disease MicrovascularInjury: Lessons from Trangenic Mice: Neurochemistry International 2001,39, 393-400) diseases.

Pharmaceutical Compositions

The compositions of the present invention are therapeutically effectiveamounts of the TGF-β antagonists, noted above. The composition may beformulated with common excipients, diluents or carriers, and compressedinto tablets, or formulated elixirs or solutions for convenient oraladministration or administered by intramuscular intravenous routes. Thecompounds can be administered transdermally and maybe formulated assustained release dosage forms and the like.

The method of treating a human patient according to the presentinvention includes administration of the TGF-β antagonists. The TGF-βantagonists are formulated into formulations which may be administeredby the oral and rectal routes, topically, parenterally, e.g., byinjection and by continuous or discontinuous intra-arterial infusion, inthe form of, for example, tablets, lozenges, sublingual tablets,sachets, cachets, elixirs, gels, suspensions, aerosols, ointments, forexample, containing from 1 to 10% by weight of the active compound in asuitable base, soft and hard gelatin capsules, suppositories, injectablesolutions and suspensions in physiologically acceptable media, andsterile packaged powders adsorbed onto a support material for makinginjectable solutions. Advantageously for this purpose, compositions maybe provided in dosage unit form, preferably each dosage unit containingfrom about 5 to about 500 mg (from about 5 to 50 mg in the case ofparenteral or inhalation administration, and from about 25 to 500 mg inthe case of oral or rectal administration) the compounds. Dosages fromabout 0.5 to about 300 mg/kg per day, preferably 0.5 to 20 mg/kg, ofactive ingredient may be administered although it will, of course,readily be understood that the amount of the compound actually to beadministered will be determined by a physician, in the light of all therelevant circumstances including the condition to be treated, the choiceof compound to be administered and the choice of route of administrationand therefore the above preferred dosage range is not intended to limitthe scope of the present invention in any way.

The formulations useful for separate administration of the TGF-βantagonists will normally consist of at least one compound selected fromthe compounds specified herein mixed with a carrier, or diluted by acarrier, or enclosed or encapsulated by an ingestible carrier in theform of a capsule, sachet, cachet, paper or other container or by adisposable container such as an ampoule. A carrier or diluent may be asolid, semi-solid or liquid material which serves as a vehicle,excipient or medium for the active therapeutic substance. Some examplesof the diluents or carrier which may be employed in the pharmaceuticalcompositions of the present invention are lactose, dextrose, sucrose,sorbitol, mannitol, propylene glycol, liquid paraffin, white softparaffin, kaolin, fumed silicon dioxide, microcrystalline cellulose,calcium silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol,starch, modified starches, gum acacia, calcium phosphate, cocoa butter,ethoxylated esters, oil of theobroma, arachis oil, alginates,tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylene sorbitanmonolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitantrioleate, sorbitan sesquioleate and oleyl alcohol and propellants suchas trichloromonofluoromethane, dichlorodifluoromethane anddichlorotetrafluoroethane. In the case of tablets, a lubricant may beincorporated to prevent sticking and binding of the powdered ingredientsin the dies and on the punch of the tableting machine. For such purposethere may be employed for instance aluminum, magnesium or calciumstearates, talc or mineral oil.

Preferred pharmaceutical forms of the present invention are capsules,tablets, suppositories, injectable solutions, creams and ointments.Especially preferred are formulations for inhalation application, suchas an aerosol, for injection, and for oral ingestion.

1. A compound of the structure

is a four, five, or six membered saturated ring and X is C, O or S withthe proviso that the ring is a fully saturated carbon ring wherein X inthe ring may be a single substitution of either C, O or S, except Xcannot be O when it would be adjacent to carbon of the pyrazolo ring andR1 is pyridine and R2 is a sulfonyl substituted phenyl or thienyl; R1 isunsubstituted or substituted phenyl; unsubstituted or substitutedpyridine; unsubstituted or substituted pyridine N-oxide; unsubstitutedor substituted quinoline; unsubstituted or substituted quinolineN-oxide; unsubstituted or substituted naphthyridine; unsubstituted orsubstituted pyrazine; furyl; unsubstituted or substituted thiazolyl;unsubstituted or substituted imidazolyl; unsubstituted or substitutedpyrazolyl; or unsubstituted or substituted thiophenyl; wherein thesubstitution may be one or more of the following: (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₂-C₆)alkenyloxy,(C₂-₆)alkynyloxy, (C₁-C₆)alkylthio, (C₁C₆)alkylsulphinyl, (C₁-C₆)alkylsulphonyl, (C₁-C₆)alkylamino, di-[(C₁-C₆)alkyl]amino,(C₁-C₆)alkoxycarbonyl, N—(C₁-C₆)alkylcarbamoyl,N,N-di-[(C₁-C₆)alkyl]carbamoyl, (C₂-C₆)alkanoyl, (C₂-C₆)alkanoyloxy,(C₂-C₆)alkanoylamino, N—(C₁-C₆)alkyl-(C₂-C₆)alkanoylamino,(C₃-C₆)alkenoylamino, N—(C₁-C₆)alkyl-(C₃-C₆)alkenoylamino,(C₃-C₆)alkynoylamino, N—(C₁-C₆) alkyl-(C₃-C₆)alkynoylamino,N—(C₁-C₆)alkylsulphamoyl, N,N-di-[(C₁-C₆)alkyl]sulphamoyl,(C₁-C₆)alkanesulphonylamino, N—(C₁-C₆)alkyl-(C₁-C₆)alkanesulphonylamino,carboxamide, thiophenyl, aminophenyl, trifluoromethyl, halo,trifluoromethoxy, hydroxymethyl, N-pyrrolidino, N-morpholino,phenylthio, (C₁-C₄)dialkylaminomethyl, methoxyphenyl, amino, hydroxy,carboxyl, phenyl, arylalky; R2 is unsubstituted or substitutedquinoline; unsubstituted or substituted quinoline N-oxide; unsubstitutedor substituted phenyl; unsubstituted or substituted naphthalene;unsubstituted or substituted pyridine; unsubstituted or substitutedpyridine N-oxide; unsubstituted or substituted quinazoline;unsubstituted or substituted cinnoline; unsubstituted or substitutedbenzodioxole; unsubstituted or substituted benzodioxane; unsubstitutedor substituted benzothiophene; or unsubstituted or substitutedphenanthroline; wherein the substitution may independently be one ormore of the following: hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylhalide, (C₁-C₆)alkoxy, (C₂-C₆)alkenyloxy,(C₂-C₆)alkynyloxy, (C₁-C₆)alkylthio, (C₁-C₆)alkylsulphinyl,(C₁-C₆)alkylsulphonyl, (C₁-C₆)alkylamino, di-[(C₁-C₆)alkyl]amino,(C₁-C₆)alkoxycarbonyl, N—(C₁-C₆)alkylcarbamoyl,N,N-di-[(C₁-C₆)alkyl]carbamoyl, aminooxy, N—(C₁-C₆)alkyl aminooxy,N,N-di-[(C₁-C₆)alkyl]aminooxy, (C₂-C₆)alkanoyl, (C₂-C₆)alkanoyloxy,(C₂-C₆)alkanoylamino, N—(C₁-C₆)alkyl-(C₂-C₆)alkanoylamino, (C₃-C₆)alkenoylamino, N—(C₁-C₆)alkyl-(C₃-C₆)alkenoylamino,(C₃-C₆)alkynoylamino, N—(C₁-C₆)alkyl-(C₃-C₆)alkynoylamino, sulphamoyl,N—(C₁-C₆)alkylsulphamoyl, N,N-di-[(C₁-C₆)alkyl]sulphamoyl,(C₁-C₆)alkanesulphonylamino, N—(C₁-C₆)alkyl-(C₁-C₆)alkanesulphonylamino,carboxamide, phenyl, thiophenyl, aminophenyl, phenylthio, halo, cyano,pyridinyl, arylalkyl, hydroxy, N-pyrrolidino, N-morpholino, carboxyl,[5-phenyl-1,2,4-oxadiazole-3-yl]methoxy, 6-methyl-pyridazin-3-yloxy,(5-oxo-2-pyrrolidinyl)methoxy, 2-(4,5-dihydro-1H-imidazolyl),N,N-dialkylcarbamoyloxy, 1-hydroxy-1-methylethyl, 4-fluorophenyl,3,4-methylenedioxyphenyl, trifluoromethyl, trifluoromethoxy, or a groupof the formula

wherein: X₁ is O, N, S, SO₂, NR₁₃, C(O), or bond; Q₁ is hydrogen,phenyl, 5-(2,2-difluoro-1,3-benzodioxolyl), C(O)Q₅, or pyridyl when, mand n are independently 0-2, except when one is 0 the other cannot be 0;Q₁, is OR, NR¹¹R¹², halo, N-morpholino, N-piperazino-N′R₁₃,N-imidazolyl, N-pyrazolyl, N-triazolyl, N-(4-piperidinylpiperidine),SO₂R₁₄, SOR₁₄, NHSO₂R₁₅, acetamido, N-phthalimido, N-oxazolidino,N-imidazolino, N-benzoxazolidino, N-pyrolidinonyl,N(N′-methylbenzimidazolino), N,N-di(C₁-C₄)alkylamino(C₁-C₄)alkoxy,N-benzimidazolino; when m and n are independently 0-2, but one or theother of m or n is not 0; Q₅ is hydroxy, methoxy, amino, diethylamino,dimethylamino; R₁₀ is hydrogen, halo, (C₁-C₆)alkyl; R₁₁ and R₁₂ areindependently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, arylalkyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkylmethyl, 4-(N-methylpiperidinyl),pyridyl, or R₁₁ and R₁₀ can be taken together to form a 4, 5, 6, or 7membered ring, or R₁₁ and R₁₂ can be taken together to form a 3, 4, 5,6, or 7 membered ring; R₁₃ is hydrogen, (C₁-C₆)alkyl, 2-methoxyphenyl,2-pyridimidinyl; R₁₄ is 2-pyrimidinyl, N-methyl-2-imidazolyl,4-chlorophenyl, 2-pyridylmethyl; R₁₅ is (C₁-C₆)alkyl,N-methyl-4-imidazolyl; R₁₆ is hydrogen, halo, arylalkyl, aryl, or agroup of the formula

wherein: Q₂ is hydrogen, 4-imidazolyl, or C(O)NR₂₄R₂₅ when o and p areindependently 0-2; Q₂ is OR₂₃, NR₂₄R₂₅, or N-morpholino, when o and pare independently 0-2, but one or the other of o or p is not 0; R₂₀ ishydrogen, or (C₁-C₆)alkyl; R₂₁ is hydrogen, (C₁-C₆)alkyl, or R₂₁ and R₂₀can be taken together to form a 4, 5, 6, or 7 membered ring; R₂₂ ishydrogen, (C₁-C₆)alkyl, arylalkyl, aryl, or R₂₁ and R₂₂ can be takentogether to be a 3, 4, 5, 6, 7 membered ring; R₂₃ is hydrogen or(C₁-C₆)alkyl; R₂₄ is hydrogen, (C₁-C₆)alkyl, or R₂₄ and R₂₅ can be takentogether to form a 3, 4, 5, 6, or 7 membered ring, or R₂₄ and R₂₀ can betaken together to form a 6 or 7 membered ring; R₂₅ is hydrogen,(C₁-C₆)alkyl, or acetyl, or a group of the formula

wherein: R₃₀ is hydrogen, or (C₁-C₆)alkyl; R₃₁ is hydrogen,(C₁-C₆)alkyl, 2-pyridyl, pyridylmethyl, amino, or hydroxy, or a group ofthe formula—NR₃₂R₃₃ wherein: R₃₂ and R₃₃ are each independently hydrogen,(C₁-C₆)alkyl, acetyl, (C₁-C₄)alkylsulphonyl, or R₃₂ and R₃₃ can be takentogether to form a 4, 5, 6, or 7 membered ring, or a group of theformula

wherein: X₂ is CH₂, O, or N; q is 0-3; Q₃ is NR₃₆R₃₇, or OR³⁸, and R³⁵is hydrogen, or R³⁵ and Q₃ can be taken together to form a 5 memberedring; R₃₆, R₃₇, and R₃₈ are each independently hydrogen, or(C₁-C₆)alkyl, or a group of the formula

wherein: X₃ is cyano, carboxamide, N,N-dimethylcarboxamide,N,N-dimethylthiocarboxamide, N,N-dimethylaminomethyl,4-methylpiperazin-1-yl-methyl or carboxylate, or a group of the formula

wherein: Q₆ is NR₄₁R₄₂; r is 2-3; R₄₀ is hydrogen, or (C₁-C₆)alkyl; R₄₁and R₄₂ are hydrogen, (C₁-C₆)alkyl, or R₄₁ and R₄₀ can be taken togetherto form a 6 or 7 membered ring, or a group of the formula

wherein: Q₇ is hydroxy, methoxy, dimethylamino, or N-piperidinyl; withthe proviso that when one of R₁ or R₂ is unsubstituted or substitutedphenyl, then the other cannot be unsubstituted or substituted phenyl orthiophen-2-yl; and with the proviso that when R₂ is quinolin-4-yl,substitution at the quinoline 7-position cannot include an aryl,heteroaryl, fused aryl, or fused heteroaryl; k is 1-8; R₃ is one or moreof the following: hydrogen; (C₁-C₄)alkyl; (C₁-C₄) alkylhydroxy; hydroxy;N,N-di(C₁-C₄alkylamino(C₁-C₄)alkoxy; benzyl oxymethyl; phenyloxymethyl;oxo; carboxyl; (C₁-C₄)alkylaryl; benzyloxy; acetoxy; amino(C₁-C₄)alkyl;(C₂-C₄)alkenyl; halo; —O—(C₁-C₄)alkyl; chlorophenethyl; acetonitrile;unsubstituted or substituted phenyl; wherein the substitution may be oneor more of the following: (C₁-C₆)alkoxy, halo, carboxy, or(C₁-C₆)alkoxycarbonyl; and the pharmaceutically acceptable salts, estersand prodrugs thereof.
 2. A compound according to claim 1 of thestructure

is a five or six membered saturated ring with the proviso that the ringis a fully saturated carbon ring; R1 is defined as in claim 1; R2 ishydrogen; (C₁-C₆)alkyl; (C₁-C₆)alkylthio; (C₁-C₆)alkoxy; halo;thiophenyl; aminophenyl; N-pyrrolidino; N-morpholino; R6′ and R7′ areindependently one or more of the following: hydrogen, (C₁-C₆) alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆) alkylhalide, (C₁-C₆)alkoxy,(C₂-C₆)alkenyloxy, (C₂-C₆)alkynyloxy, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulphinyl, (C₁-C₆) alkylsulphonyl, (C₁-C₆)alkylamino,di-[(C₁-C₆)alkyl]amino, (C₁-C₆)alkoxycarbonyl, N—(C₁-C₆)alkylcarbamoyl,N,N-di-[(C₁-C₆)alkyl]carbamoyl, aminooxy, N—(C₁-C₆)alkyl aminooxy,N,N-di-[(C₁-C₆)alkyl]aminooxy, (C₂-C₆)alkanoyl, (C₂-C₆)alkanoyloxy,(C₂-C₆)alkanoylamino, N—(C₁-C₆)alkyl-(C₂-C₆)alkanoylamino, (C₃-C₆)alkenoylamino, N—(C₁-C₆) alkyl-(C₃-C₆)alkenoylamino,(C₃-C₆)alkynoylamino, N—(C₁-C₆)alkyl-(C₃-C₆)alkynoylamino, sulphamoyl,N—(C₁-C₆)alkylsulphamoyl, N,N-di-[(C₁-C₆) alkyl]sulphamoyl,(C₁-C₆)alkanesulphonylamino, N—(C₁-C₆)alkyl-(C₁-C₆)alkanesulphonylamino, carboxamide, phenyl, thiophenyl, aminophenyl,phenylthio, halo, cyano, pyridinyl, arylalkyl, hydroxy, N-pyrrolidino,N-morpholino, carboxyl, [5-phenyl-1,2,4-oxadiazole-3-yl]methoxy,6-methyl-pyridazin-3-yloxy, (5-oxo-2-pyrrolidinyl)methoxy,2-(4,5-dihydro-1H-imidazolyl), N,N-dialkylcarbamoyloxy,1-hydroxy-1-methylethyl, 4-fluorophenyl, 3,4-methylenedioxyphenyl,trifluoromethyl, trifluoromethoxy, or a group of the formula

wherein: X₁ is O, N, S, SO₂, NR₁₃, C(O), or bond; Q₁ is hydrogen,phenyl, 5-(2,2-difluoro-1,3 -benzodioxolyl), C(O)Q₅, or pyridyl when mand n are independently 0-2, except when one is 0 the other cannot be 0;Q₁ is OR₁₁, NR₁₁R₁₂, halo, N-morpholino, N-piperazino-N′R₁₃,N-imidazolyl, N-pyrazolyl, N-triazolyl, N-(4-piperidinylpiperidine),SO₂R₁₄, SOR₄, NHSO₂R₁₅, acetamido, N-phthalimido, N-oxazolidino,N-imidazolino, N-benzoxazolidino, N-pyrolidinonyl,N(N′-methylbenzimidazolino), N,N-di(C₁-C₄)alkylamino(C₁-C₄)alkoxy,N-benzimidazolino; when m and n are independently 0-2, but one or theother of m or n is not 0; Q₅ is hydroxy, methoxy, amino, diethylamino,dimethylamino; R₁₀ is hydrogen, halo, (C₁-C₆)alkyl; R₁₁ and R₁₂ areindependently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, arylalkyl,cycloalkyl, cycloalkylmethyl, 4-(N-methylpiperidinyl), pyridyl, or R₁₁and R₁₀ can be taken together to form a 4, 5, 6, or 7 membered ring, orR₁₁ and R₁₂ can be taken together to form a 3, 4, 5, 6, or 7 memberedring; R₁₃ is hydrogen, (C₁-C₆)alkyl, 2-methoxyphenyl; R₁₄ is2-pyrimidinyl, N-methyl-2-imidazolyl, 4-chlorophenyl, 2-pyridylmethyl;R₁₅ is (C₁-C₆) alkyl, N-methyl-4-imidazolyl; R₁₆ is hydrogen, halo,arylalkyl, aryl, or a group of the formula

wherein: Q₂ is hydrogen, 4-imidazolyl, or C(O)NR₂₄R₂₅ when o and p areindependently 0-2; Q₂ is OR₂₃, NR₂₄R₂₅, or N-morpholino, when o and pare independently 0-2, but one or the other of o or p is not 0; R₂₀ ishydrogen, or (C₁-C₆)alkyl; R₂₁ is hydrogen, (C₁-C₆)alkyl, or R₂₁ and R₂₀can be taken together to form a 4, 5, 6, or 7 membered ring; R₂₂ ishydrogen, (C₁-C₆)alkyl, arylalkyl, aryl, or R₂₁ and R₂₂ can be takentogether to be a 3, 4, 5, 6, 7 membered ring; R₂₃ is hydrogen or(C₁-C₆)alkyl; R₂₄ is hydrogen, (C₁-C₆)alkyl, or R₂₄ and R₂₅ can be takentogether to form a 3, 4, 5, 6, or 7 membered ring, or R₂₄ and R₂₀ can betaken together to form a 6 or 7 membered ring; R₂₅ is hydrogen,(C₁-C₆)alkyl, or acetyl, or a group of the formula

wherein: R₃₀ is hydrogen, or (C₁-C₆)alkyl; R₃ is hydrogen, (C₁-C₆)alkyl,2-pyridyl, pyridylmethyl, amino, or hydroxy, or a group of the formula—NR₃₂R₃₃ wherein: R₃₂ and R₃₃ are each independently hydrogen,(C₁-C₆)alkyl, acetyl, alkylsulphonyl, or R₃₂ and R₃₃ can be takentogether to form a 4, 5, 6, or 7 membered ring, or a group of theformula

wherein: X₂ is CH₂, O, or N; q is 0-3; Q₃ is NR₃₆R₃₇, or OR₃₈; R₃₅ ishydrogen, or R₃₅ and Q₃ (when Q₃ is a bond) can be taken together toform a 5 membered ring; R₃₆, R₃₇, and R₃₈ are each independentlyhydrogen, or (C₁-C₆)alkyl, or a group of the formula

wherein: X₃ is cyano, carboxamide, N,N-dimethylcarboxamide,N,N-dimethylthiocarboxamide, N,N-dimethylaminomethyl,4-methylpiperazin-1-yl-methyl or carboxylate, or a group of the formula

wherein: Q₆ is NR₄₁R₄₂; r is 2-3; R₄₀ is hydrogen, or (C₁-C₆)alkyl; R₄₁and R₄₂ are hydrogen, (C₁-C₆)alkyl, or R₄₁ and R₄₀ can be taken togetherto form a 6 or 7 membered ring, or a group of the formula

wherein: Q₇ is hydroxy, methoxy, or N-piperidinyl; k is 1-8; R₃ is oneor more of the following: hydrogen; (C₁-C₄) alkyl; (C₁-C₄) alkylhydroxy;hydroxy; N,N-di(C₁-C₄)alkylamino(C₁-C₄)alkoxy; benzyl oxymethyl;phenyloxymethyl; oxo; carboxyl; (C₁-C₄)alkylaryl; benzyloxy; acetoxy;amino(C₁-C₄)alkyl; (C₂-C₄)alkenyl; halo; —O—(C₁-C₄)alkyl;chlorophenethyl; acetonitrile; phenyl; or an optionally substitutedphenyl; wherein the substitution may be one or more of the following:(C₁-C₆)alkoxy, halo, carboxy, or (C₁-C₆)alkoxycarbonyl; with the provisothat R₇ cannot be aryl; heteroaryl; fused aryl; or fused heteroaryl, andthe pharmaceutically acceptable salts, esters and prodrugs thereof.
 3. Acompound according to claim 1 of the structure

is a five or six membered saturated ring, with the proviso that the ringis a fully saturated carbon ring; R1 is defined as in claim 1; R3″ ishydrogen; halo; trifluoromethyl; R4″ is hydrogen; halo; (C₁-C₆)alkyl;(C₁-C₆)alkoxy; hydroxy; (C₁-C₆)alkylsulphonyl; k and R3 are defined asin claim 1; and the pharmaceutically acceptable salts, esters andprodrugs thereof.
 4. A compound according to claim 1 of the structure

is a five or six membered saturated ring, with the proviso that the ringis a fully saturated carbon ring; R6 may be one or more of thefollowing: hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkoxy, (C₂-C₆)alkenyloxy, (C₂-C₆)alkynyloxy, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulphinyl, (C₁-C₆)alkylsulphonyl, (C₁-C₆)alkylamino,di-[(C₁-C₆)alkyl]amino, (C₁-C₆)alkoxycarbonyl, N—(C₁-C₆)alkylcarbamoyl,N,N-di-[(C₁-C₆)alkyl]carbamoyl, (C₂-C₆)alkanoyl, (C₂-C₆)alkanoyloxy,(C₂-C₆)alkanoylamino, N—(C₁-C₆)alkyl -(C₂-C₆)alkanoylamino,(C₃-C₆)alkenoylamino, N—(C₁-C₆)alkyl-(C₃-C₆)alkenoylamino,(C₃-C₆)alkynoylamino, N—(C₁-C₆)alkyl-(C₃-C₆)alkynoylamino,N—(C₁-C₆)alkylsulphamoyl, N,N-di-[(C₁-C₆)alkyl] sulphamoyl,(C₁-C₆)alkanesulphonylamino, N—(C₁-C₆)alkyl-(C₁-C₆)alkanesulphonylamino, carboxamide, thiophenyl, aminophenyl,trifluoromethyl, halo, trifluoromethoxy, hydroxymethyl, N-pyrrolidino,N-morpholino, phenylthio, dialkylaminomethyl, methoxyphenyl, amino,hydroxy, carboxyl, phenyl, arylalky; R2″ is unsubstituted or substitutedquinoline-8-yl; unsubstituted or substituted quinoline-6-yl;unsubstituted or substituted 1-naphthyl; unsubstituted or substituted2-naphthyl; unsubstituted or substituted 3,4-methylenedioxyphenyl;unsubstituted or substituted 3,4-ethylenedioxyphenyl; unsubstituted orsubstituted benzothiophen-2-yl; wherein the substitution mayindependently be one or more of the following: (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆) alkylhalide, (C₁-C₆)alkoxy,(C₂-C₆)alkenyloxy, (C₂-C₆)alkynyloxy, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulphinyl, (C₁-C₆)alkylsulphonyl, (C₁-C₆) alkylamino,di-[(C₁-C₆)alkyl]amino, (C₁-C₆)alkoxycarbonyl, N—(C₁-C₆)alkylcarbamoyl,N,N-di-[(C₁-C₆)alkyl]carbamoyl, aminooxy, N—(C₁-C₆)alkyl aminooxy,N,N-di-[(C₁-C₆)alkyl]aminooxy, (C₂-C₆)alkanoyl, (C₂-C₆)alkanoyloxy,(C₂-C₆)alkanoylamino, N—(C₁-C₆)alkyl-(C₂-C₆)alkanoylamino,(C₃-C₆)alkenoylamino, N—(C₁-C₆)alkyl -(C₃-C₆)alkenoylamino,(C₃-C₆)alkynoylamino, N—(C₁-C₆)alkyl-(C₃-C₆)alkynoylamino, sulphamoyl,N—(C₁-C₆)alkylsulphamoyl, N,N-di-[(C₁-C₆)alkyl]sulphamoyl, (C₁-C₆)alkanesulphonylamino, N—(C₁-C₆)alkyl-(C₁-C₆)alkanesulphonylamino,carboxamide, ethylene, phenyl, thiophenyl, aminophenyl, phenylthio,halo, cyano, pyridinyl, arylalkyl, hydroxy, N-pyrrolidino, N-morpholino,carboxyl, [5-phenyl-1,2,4-oxadiazole-3-yl]methoxy,6-methyl-pyridazin-3-yloxy, (5-oxo-2-pyrrolidinyl)methoxy,2-(4,5-dihydro-1-H-imidazolyl), N,N-dialkylcarbamoyloxy,1-hydroxy-1-methylethyl, 4-fluorophenyl, 3,4-methylenedioxyphenyl,trifluoromethyl, trifluoromethoxy, or a group of the formula

wherein: X₁ is O, N, S, SO₂, NR₁₃, C(O), or bond; Q₁ is hydrogen,phenyl, 5-(2,2-difluoro-1,3-benzodioxolyl), C(O)Q₅, or pyridyl when mand n are independently 0-2, except when one is 0 the other cannot be 0;Q₁ is OR₁, NR₁₁R₁₂, halo, N-morpholino, N-piperazino-N′R₁₃,N-imidazolyl, N-pyrazolyl, N-triazolyl, N-(4-piperidinylpiperidine),SO₂R₁₄, SOR₁₄, NHSO₂R₁₅, acetamido, N-phthalimido, N-oxazolidino,N-imidazolino, N-benzoxazolidino, N-pyrolidinonyl,N(N′-methylbenzimidazolino), N,N-di(C₁-C₄)alkylamino(C₁-C₄)alkoxy,N-benzimidazolino; when m and n are independently 0-2, but one or theother of m or n is not 0; Q₅ is hydroxy, methoxy, amino, diethylamino,dimethylamino; R₁₀ is hydrogen, halo, (C₁-C₆)alkyl; R₁₁ and R₁₂ areindependently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, arylalkyl,cycloalkyl, cycloalkylmethyl, 4-(N-methylpiperidinyl), pyridyl, or R₁₁and R₁₀ can be taken together to form a 4, 5, 6, or 7 membered ring, orR₁₁ and R₁₂ can be taken together to form a 3, 4, 5, 6, or 7 memberedring; R₁₃ is hydrogen, (C₁-C₆)alkyl, 2-methoxyphenyl; R₁₄ is2-pyrimidinyl, N-methyl-2-imidazolyl, 4-chlorophenyl, 2-pyridylmethyl;R₁₅ is (C₁-C₆)alkyl, N-methyl-4-imidazolyl; R₁₆ is hydrogen, halo,arylalkyl, aryl, or a group of the formula

wherein: Q₂ is hydrogen, 4-imidazolyl, or C(O)NR₂₄R₂₅ when o and p areindependently 0-2; Q₂ is OR₂₃, NR₂₄R₂₅, or N-morpholino, when o and pare independently 0-2, but one or the other of o or p is not 0; R₂₀ ishydrogen, or (C₁-C₆)alkyl; R₂₁ is hydrogen, (C₁-C₆)alkyl, or R₂₁ and R₂₀can be taken together to form a 4, 5, 6, or 7 membered ring; R₂₂ ishydrogen, (C₁-C₆)alkyl, arylalkyl, aryl, or R₂₁ and R₂₂ can be takentogether to be a 3, 4, 5, 6, 7 membered ring; R₂₃ is hydrogen or(C₁-C₆)alkyl; R₂₄ is hydrogen, (C₁-C₆)alkyl, or R₂₄ and R₂₅ can be takentogether to form a 3, 4, 5, 6, or 7 membered ring, or R₂₄ and R₂₀ can betaken together to form a 6 or 7 membered ring; R₂₅ is hydrogen,(C₁-C₆)alkyl, or acetyl, or a group of the formula

wherein: R₃₀ is hydrogen, or (C₁-C₆)alkyl; R₃₁ is hydrogen,(C₁-C₆)alkyl, 2-pyridyl, pyridylmethyl, amino, or hydroxy, or a group ofthe formula—NR₃₂R₃₃ wherein: R₃₂ and R₃₃ are each independently hydrogen,(C₁-C₆)alkyl, acetyl, alkylsulphonyl, or R₃₂ and R₃₃ can be takentogether to form a 4, 5, 6, or 7 membered ring, or a group of theformula

wherein: X₂ is CH₂, O, or N; q is 0-3; Q₃ is NR₃₆R₃₇ or OR₃₈; R₃₅ ishydrogen, or R₃₅ and Q₃ (when Q₃ is a bond) can be taken together toform a 5 membered ring; R₃₆, R₃₇, and R₃₈ are each independentlyhydrogen, or (C₁-C₆)alkyl, or a group of the formula

wherein: X₃ is cyano, carboxamide, N,N-dimethylcarboxamide, N,Ndimethylthiocarboxamide, N,N-dimethylaminomethyl, 4-methylpiperazin-1yl-methyl or carboxylate, or a group of the formula

wherein: Q₆ is NR₄₁R₄₂; r is 2-3; R₄₀ is hydrogen, or (C₁-C₆)alkyl; R₄₁and R₄₂ are hydrogen, (C₁-C₆)alkyl, or R₄₁ and R₄₀ can be taken togetherto form a 6 or 7 membered ring, or a group of the formula

wherein: Q₇ is hydroxy, methoxy, dimethylamino, or N-piperidinyl; k is1-8; R₃ is hydrogen; and the pharmaceutically acceptable salts thereof.5. A pharmaceutical formulation comprising a compound according to claim1 or a pharmaceutically acceptable salt, ester or prodrug thereoftogether with a pharmaceutically acceptable diluent or carrier.
 6. Amethod of treating cancer which comprises administering to a patient inneed thereof a therapeutically effective amount of a compound accordingto claim 1 or a pharmaceutically acceptable salt, ester or prodrugthereof.
 7. A method of treating cancer which comprises administering toa patient in need thereof a therapeutically effective amount of acompound according to claim 1 or a pharmaceutically acceptable salt,ester or prodrug thereof in combination with any other anti-canceragent.